Crystalline solid forms of a BET inhibitor

ABSTRACT

The present application relates to crystalline solid forms of an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t, including methods of preparation thereof, and intermediates in the preparation thereof, where the compound is useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present application relates to crystalline solid forms of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one,which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, andBRD-t, including methods of preparation thereof, and intermediates inthe preparation thereof, where the compound is useful in the treatmentof diseases such as cancer.

BACKGROUND OF THE INVENTION

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. DNA is packaged into chromatin by wrapping around acore of histone proteins to form a nucleosome. These nucleosomes arefurther compacted by aggregation and folding to form a highly condensedchromatin structure. A range of different states of condensation arepossible, and the tightness of this structure varies during the cellcycle, being most compact during the process of cell division. Chromatinstructure plays a critical role in regulating gene transcription byregulating protein access to the DNA. The chromatin structure iscontrolled by a series of post translational modifications to histoneproteins, mainly within the tails of histones H3 and H4 that extendbeyond the core nucleosome structure. These reversible modificationsinclude acetylation, methylation, phosphorylation, ubiquitination andSUMOylation. These epigenetic marks are written and erased by specificenzymes that modify specific residues within the histone tail, therebyforming an epigenetic code. Other nuclear proteins bind to these marksand effect outputs specified by this information through the regulationof chromatin structure and gene transcription. Increasing evidence linksgenetic changes to genes encoding epigenetic modifiers and regulatorsleading to aberrant histone marks in diseases such as neurodegenerativedisorders, metabolic diseases, inflammation and cancer.

Histone acetylation is typically associated with the activation of genetranscription, as the modification weakens the interaction between theDNA and the histone proteins, permitting greater access to DNA by thetranscriptional machinery. Specific proteins bind to acetylated lysineresidues within histones to “read” the epigenetic code. A highlyconserved protein module called the bromodomain binds to acetylatedlysine residues on histone and other proteins. There are more than 60bromodomain-containing proteins in the human genome.

The BET (Bromodomain and Extra-Terminal) family of bromodomaincontaining proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t)that share a conserved structural organization containing tandemN-terminal bromodomains capable of binding to acetylated lysine residuesof histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitouslyexpressed while BRDt is restricted to germ cells. BRD proteins playessential, but non-overlapping roles in regulating gene transcriptionand controlling cell growth. BET proteins are associated with largeprotein complexes including Mediator, PAFc and super elongation complexthat regulate many aspects of gene transcription. BRD2 and BRD4 proteinshave been shown to remain in complex with chromosomes during mitosis andare required to promote transcription of critical genes including cyclinD and c-Myc that initiate the cell cycle (Mochizuki J Biol. Chem. 2008283:9040-9048). BRD4 is essential for recruiting the proteintranslational elongation factor B complex to the promoters of induciblegenes resulting in the phosphorylation of RNA polymerase II andstimulating productive gene transcription and elongation (Jang et al.Mol. Cell 2005 19:523-534). In some instances, a kinase activity of BRD4may directly phosphorylate and activate RNA polymerase II (Devaiah etal. PNAS 2012 109:6927-6932). Cells lacking BRD4 show impairedprogression through cell cycle. BRD2 and BRD3 are reported to associatewith histones along actively transcribed genes and may be involved infacilitating transcriptional elongation (Leroy et al, Mol. Cell. 200830:51-60). In addition to acetylated histones, BET proteins have beenshown to bind selectively to acetylated transcription factors includingthe RelA subunit of NF-kB and GATA1 thereby directly regulating thetranscriptional activity of these proteins to control expression ofgenes involved in inflammation and hematopoietic differentiation (Huanget al, Mol. Cell. Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad.Sci. 2011 108:E159-168).

A recurrent translocation involving NUT (nuclear protein in testes) withBRD3 or BRD4 to form a novel fusion oncogene, BRD-NUT, is found in ahighly malignant form of epithelial neoplasia (French et al, CancerResearch 2003 63:304-307; French et al, Journal of Clinical Oncology2004 22:4135-4139). Selective ablation of this oncogene restores normalcellular differentiation and reverses the tumorigenic phenotype(Filippakopoulos et al, Nature 2010 468:1068-1073). Genetic knockdown ofBRD2, BRD3 and BRD4 has been shown to impair the growth and viability ofa wide range of hematological and solid tumor cells (Zuber et al, Nature2011 478:524-528; Delmore et al, Cell 2011 146:904-917). Aside from arole in cancer, BET proteins regulate inflammatory responses tobacterial challenge, and a BRD2 hypomorph mouse model showeddramatically lower levels of inflammatory cytokines and protection fromobesity induced diabetes (Wang et al Biochem J. 2009 425:71-83; Belkinaet al. J. Immunol 2013). In addition, some viruses make use of these BETproteins to tether their genomes to the host cell chromatin, as part ofthe process of viral replication or use BET proteins to facilitate viralgene transcription and repression (You et al, Cell 2004 117:349-60; Zhuet al, Cell Reports 2012 2:807-816).

Inhibitors of BET proteins are in current development. Exemplary BETprotein inhibitors are disclosed in, for example, U.S. Pat. App. Pub.Nos. 2014/0275030; 2015/0011540; 2015/0148375; 2015/0148342;2015/0148372; 2015/0175604; and 2016/007572. In particular, theBET-inhibiting compound2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-oneis described in US 2015/0307493. For the development of a drug, it istypically advantageous to employ a form of the drug having desirableproperties with respect to its preparation, purification,reproducibility, stability, bioavailability, and other characteristics.Accordingly, the solid crystalline forms of the compound provided hereinhelp satisfy the ongoing need for the development of BET inhibitors forthe treatment of diseases.

SUMMARY OF THE INVENTION

The present application provides, inter alia, crystalline solid forms ofan inhibitor of a BET protein, wherein the inhibitor is2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one.

The present application also provides pharmaceutical compositionscomprising a crystalline solid form of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-oneand at least one pharmaceutically acceptable carrier.

The present application also provides methods of using a crystallinesolid form of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-onein the treatment of diseases and disorders associated with activity ofBET proteins

Further, the present application provides methods of preparing2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-oneand crystalline solid forms thereof.

Furthermore, the present application provides intermediate compounds,and methods for their preparation, useful in the synthesis of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of Form I ofCompound 1.

FIG. 2 is a differential scanning calorimetry (DSC) thermogram of Form Iof Compound 1.

FIG. 3 is a thermogravimetric analysis (TGA) thermogram of Form I ofCompound 1.

FIG. 4 is an XRPD pattern of Form II of Compound 1.

FIG. 5 is a DSC thermogram of Form II of Compound 1.

FIG. 6 is a TGA thermogram of Form II of Compound 1.

FIG. 7 is an XRPD pattern of Form Ia of Compound 1.

FIG. 8 is an XRPD pattern of Form III of Compound 1.

FIG. 9 is an XRPD pattern of Form IV of Compound 1.

FIG. 10 is an XRPD pattern of Form V of Compound 1.

FIG. 11 is an XRPD pattern of Form Va of Compound 1.

FIG. 12 is an XRPD pattern of Form VI of Compound 1.

FIG. 13 is an XRPD pattern of Form VII of Compound 1.

FIG. 14 is an XRPD pattern of Form VIII of Compound 1.

FIG. 15 is an XRPD pattern of Form IX of Compound 1.

FIG. 16 is an XRPD pattern of Form X of Compound 1.

FIG. 17 is an XRPD pattern of Form XI of Compound 1.

FIG. 18 is an XRPD pattern of Form XII of Compound 1.

FIG. 19 is an XRPD pattern of Form XIII of Compound 1.

FIG. 20 is an XRPD pattern of Form XIV of Compound 1.

FIG. 21 is an XRPD pattern of Form XV of Compound 1.

DETAILED DESCRIPTION

Crystalline Forms and Processes for Their Preparation

The present application provides, inter alia, crystalline solid forms ofan inhibitor of a BET protein, wherein the inhibitor is2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(see below), referred to herein as “Compound 1”:

Typically, different crystalline forms of the same substance havedifferent bulk properties relating to, for example, hygroscopicity,solubility, stability, and the like. Forms with high melting pointsoften have good thermodynamic stability which is advantageous inprolonging shelf-life drug formulations containing the solid form. Formswith lower melting points often are less thermodynamically stable, butare advantageous in that they have increased water solubility,translating to increased drug bioavailability. Forms that are weaklyhygroscopic are desirable for their stability to heat and humidity andare resistant to degradation during long storage. Anhydrous forms areoften desirable because they can be consistently made without concernfor variation in weight or composition due to varying solvent or watercontent. On the other hand, hydrated or solvated forms can beadvantageous in that they are less likely to be hygroscopic and may showimproved stability to humidity under storage conditions.

The crystalline solid forms of the present invention can include solventsuch as water (e.g., a hydrated form) or be substantially free of waterand solvent (e.g., forming an anhydrate). In some embodiments, thecrystalline solid form is an anhydrate. In further embodiments, thecrystalline solid form is hydrated.

Compound 1 can be obtained in a solid crystalline form referred to asForm I, which is described below and in the Examples. Experimental datashow that Form I is an anhydrate. Form I is characterized by its XRPDpattern and other solid state characteristics. In some embodiments, FormI has a characteristic XRPD peak, in terms of 2-theta, at about 12.7degrees. In some embodiments, Form I has one or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 8.7, about 9.8, andabout 12.7 degrees. In some embodiments, Form I has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 8.7,about 9.8, about 12.7, about 21.4, and about 23.3 degrees.

In some embodiments, Form I has two or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.7, about 9.8, about 12.7,about 21.4, and about 23.3 degrees.

In some embodiments, Form I has two or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.7, about 9.8, about 11.6,about 12.7, about 14.7, about 15.7, about 20.0, about 21.4, about 23.3,and about 27.1 degrees.

In some embodiments, Form I has three or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.7, about 9.8, about 11.6,about 12.7, about 14.7, about 15.7, about 20.0, about 21.4, about 23.3,and about 27.1 degrees.

In some embodiments, Form I has four or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.7, about 9.8, about 11.6,about 12.7, about 14.7, about 15.7, about 20.0, about 21.4, about 23.3,and about 27.1 degrees.

In some embodiments, Form I has an XRPD pattern substantially as shownin FIG. 1.

In some embodiments, Form I has a DSC thermogram characterized by anendothermic peak at a temperature of about 266° C. In some embodiments,Form I has a DSC thermogram substantially as shown in FIG. 2.

In some embodiments, Form I has a TGA thermogram substantially as shownin FIG. 3.

Form I can be generally prepared by precipitating Form I from a solutioncomprising Compound 1 and a solvent. In some embodiments, the solventcomprises methanol, acetone, n-heptane, or a mixture thereof. Forexample, Form 1 can be prepared by precipitating Form I from a solutioncomprising Compound I and acetone. The preparation of Form I can includeadding Compound 1 to a saturated solution of Compound 1 in acetone andstirring the resulting solution at about 25° C. for about 3 days.

In some embodiments, the precipitating of Form I is carried out by (1)reducing the temperature of the solution of Compound 1 (e.g., thesolution of Compound 1 at elevated temperature), (2) concentrating thesolution of Compound 1, (3) adding an anti-solvent to the solution ofCompound 1, or any combination thereof. In some embodiments, theprecipitating is carried out by adding the anti-solvent to the solutionof Compound 1, wherein said solution of Compound 1 comprises a proticsolvent and an aprotic solvent. In some embodiments, the protic solventis methanol, the aprotic solvent is acetone, and the anti-solvent isn-heptane. In some embodiments, the precipitating of Form I is carriedout by adding n-heptane to the solution of Compound 1, wherein saidsolution of Compound 1 comprises a methanol and acetone.

In some embodiments, the preparation of Form I comprises:

(ia) heating the solution of Compound 1 to a temperature of about 50° C.to about 60° C.;

(iia) reducing the volume of the solution of Compound 1 at thetemperature of about 50° C. to about 60° C. to form a reduced-volumesolution of Compound 1;

(iiia) adding an anti-solvent to the reduced-volume solution of Compound1 while maintaining the temperature at about 55° C. to about 65° C. toform a warm solution of Compound 1; and

(iva) cooling the warm solution of Compound 1 to a temperature of about15° C. to about 30° C. to precipitate Form I.

In some embodiments, the preparation of Form I comprises:

(ib) heating the solution of Compound 1, wherein the solution comprisesmethanol and acetone as solvent, to a temperature of about 50° C. toabout 60° C.;

(iib) reducing the volume of the solution of Compound 1 at thetemperature of about 50° C. to about 60° C. to form a reduced-volumesolution of Compound 1;

(iiib) adding n-heptane to the reduced-volume solution of Compound 1while maintaining the temperature at about 55° C. to about 65° C. toform a warm solution of Compound 1; and

(ivb) cooling the warm solution of Compound 1 to a temperature of about15° C. to about 30° C. to precipitate Form I.

Compound 1 can also be obtained as a crystalline form referred to asForm II, which is described below and in the Examples. Experimental datashow that Form II is an anhydrate.

Form II is characterized by its XRPD pattern and other solid statecharacteristics. In some embodiments, Form II has a characteristic XRPDpeak, in terms of 2-theta, at about 17.0 degrees. In some embodiments,Form II has one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 17.0 and about 19.3 degrees. In some embodiments,Form II has one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 16.2, about 17.0, and about 19.3 degrees.

In some embodiments, Form II has two or more characteristic XRPD peaks,in terms of 2-theta, selected from about 6.7, about 9.5, about 10.5,about 14.8, about 16.2, about 17.0, about 18.8, and about 19.3 degrees.

In some embodiments, Form II has three or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 6.7, about 9.5, about10.5, about 14.8, about 16.2, about 17.0, about 18.8, and about 19.3degrees.

In some embodiments, Form II has four or more characteristic XRPD peaks,in terms of 2-theta, selected from about 6.7, about 9.5, about 10.5,about 14.8, about 16.2, about 17.0, about 18.8, and about 19.3 degrees.

In some embodiments, Form II has an XRPD pattern substantially as shownin FIG. 4.

In some embodiments, Form II has a DSC thermogram characterized by anendothermic peak at a temperature of about 268° C. In some embodiments,Form II has a DSC thermogram substantially as shown in FIG. 5.

In some embodiments, Form II has a TGA thermogram substantially as shownin FIG. 6.

Form II can be generally prepared by precipitating Form II from asolution comprising Compound I and a solvent. In some embodiments, thesolvent comprises tetrahydrofuran (THF), acetone, n-heptane, or amixture thereof. In some embodiments, the precipitating of Form II iscarried out (1) reducing the temperature of the solution of Compound 1,(2) concentrating the solution of Compound 1, (3) adding an anti-solventto the solution of Compound 1, or any combinations thereof. In someembodiments, the precipitating of Form II is carried out by adding theanti-solvent to the solution of Compound 1, wherein said solutioncomprises an ether solvent and an aprotic solvent. In some embodiments,the ether solvent is THF, the aprotic solvent is acetone, and theanti-solvent is n-heptane. In some embodiments, the precipitating ofForm II is carried out by adding n-heptane to the solution of Compound1, wherein said solution of Compound 1 comprises THF and acetone.

In some embodiments, the preparation of Form II comprises:

(ic) heating the solution of Compound 1 to a temperature of about 50° C.to about 60° C.;

(iic) reducing the volume of the solution of Compound 1 at thetemperature of about 50° C. to about 60° C. to form a reduced-volumesolution of Compound 1;

(iiic) adding an anti-solvent to the reduced-volume solution of Compound1 while maintaining the temperature at about 55° C. to about 65° C. toform a warm solution of Compound 1; and

(ivc) cooling the warm solution of Compound 1 to a temperature of about15° C. to about 30° C. to precipitate Form II.

In some embodiments, the preparation of Form II comprises:

(id) heating the solution of Compound 1, wherein the solution comprisesTHF and acetone as solvent, to a temperature of about 50° C. to about60° C.;

(iid) reducing the volume of the solution of Compound 1 at a temperatureof about 50° C. to about 60° C. to form a reduced-volume solution ofCompound 1;

(iiid) adding n-heptane to the reduced-volume solution of Compound 1while maintaining the temperature at about 55° C. to about 65° C. toform a warm solution of Compound 1; and

(ivd) cooling the warm solution of Compound 1 to a temperature of about15° C. to about 30° C. to precipitate Form II.

Compound 1 can also be obtained in solid crystalline forms referred toas Forms Ia, III, IV, V, Va, VI, VII, VIII, IX, X, XI, XII, XIII, XIV,and XV, which are described below and in the Examples. Forms Ia, III,IV, V, Va, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, and XV arecharacterized by their XRPD pattern and other solid statecharacteristics.

In some embodiments, Form Ia has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.8, about 10.0, about 11.7,about 12.8, and about 13.5 degrees. In some embodiments, Form Ia has oneor more characteristic XRPD peaks, in terms of 2-theta, selected fromabout 8.8, about 10.0, about 11.7, about 12.8, about 13.5, about 20.0,about 21.5, about 22.6, and about 23.3 degrees. In some embodiments,Form Ia has an XRPD pattern substantially as shown in FIG. 7.

In some embodiments, Form III has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 7.8, about 12.4, about 13.1,about 15.2, and about 15.5 degrees. In some embodiments, Form III hasone or more characteristic XRPD peaks, in terms of 2-theta, selectedfrom about 7.8, about 12.4, about 13.1, about 15.2, about 15.5, about16.9, about 17.5, and about 20.3 degrees. In some embodiments, Form IIIhas an XRPD pattern substantially as shown in FIG. 8.

In some embodiments, Form IV has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 11.2, about 16.3, about 18.7,and about 22.1 degrees. In some embodiments, Form IV has an XRPD patternsubstantially as shown in FIG. 9.

In some embodiments, Form V has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.2, about 8.5, about 14.1,about 16.3, and about 17.1 degrees. In some embodiments, Form V has oneor more characteristic XRPD peaks, in terms of 2-theta, selected fromabout 8.2, about 8.5, about 14.1, about 16.3, about 17.1, about 18.9,about 19.8, about 21.8, and about 22.7 degrees. In some embodiments,Form V has an XRPD pattern substantially as shown in FIG. 10.

In some embodiments, Form Va has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.7, about 16.5, about 17.3,about 19.9, and about 21.6 degrees. In some embodiments, Form Va has anXRPD pattern substantially as shown in FIG. 11. In some embodiments,Form Va has a DSC thermogram characterized by an endothermic peak at atemperature of about 133° C., an endothermic peak at a temperature ofabout 267° C., or a combination thereof.

In some embodiments, Form VI has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.5, about 9.6, about 11.4, andabout 12.1 degrees. In some embodiments, Form VI has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 8.5,about 9.6, about 11.4, about 12.1, about 13.5, about 14.5, about 15.2,about 17.1, about 17.7, about 18.1, about 19.2, and about 20.7 degrees.In some embodiments, Form VI has an XRPD pattern substantially as shownin FIG. 12.

In some embodiments, Form VII has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 9.9, about 12.2, about 14.8,and about 15.7 degrees. In some embodiments, Form VII has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 9.9,about 12.2, about 14.8, about 15.7, about 17.0, about 17.5, and about18.8 degrees. In some embodiments, Form VII has an XRPD patternsubstantially as shown in FIG. 13. In some embodiments, Form VII has aDSC thermogram characterized by an endothermic peak at a temperature ofabout 126° C., an endothermic peak at a temperature of about 256° C., anexothermic peak at a temperature of about 260° C., an endothermic peakat a temperature of about 267° C., or a combination thereof.

In some embodiments, Form VIII has one or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 8.1, about 8.5, about16.2, and about 17.0 degrees. In some embodiments, Form VIII has one ormore characteristic XRPD peaks, in terms of 2-theta, selected from about8.1, about 8.5, about 16.2, about 16.6, about 17.0, about 17.5, about18.0, about 18.9, about 19.6, and about 20.1 degrees. In someembodiments, Form VIII has an XRPD pattern substantially as shown inFIG. 14. In some embodiments, Form VIII has a DSC thermogramcharacterized by an endothermic peak at a temperature of about 145° C.,an endothermic peak at a temperature of about 265° C., or a combinationthereof.

In some embodiments, Form IX has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.6, about 9.1, about 11.4,about 13.4, and about 15.2 degrees. In some embodiments, Form IX has oneor more characteristic XRPD peaks, in terms of 2-theta, selected fromabout 8.6, about 9.1, about 11.4, about 13.4, about 15.2, about 18.2,about 22.1, about 22.8, and about 23.9 degrees. In some embodiments,Form IX has an XRPD pattern substantially as shown in FIG. 15.

In some embodiments, Form X has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 14.9, about 15.3, about 15.8,and about 17.0 degrees. In some embodiments, Form X has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about14.9, about 15.3, about 15.8, about 17.0, about 17.7, about 18.3, andabout 19.7 degrees. In some embodiments, Form X has an XRPD patternsubstantially as shown in FIG. 16. In some embodiments, Form X has a DSCthermogram characterized by an endothermic peak at a temperature ofabout 121° C., an endothermic peak at a temperature of about 267° C., ora combination thereof.

In some embodiments, Form XI has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 8.9, about 12.8, about 18.0about 21.5, about 22.6, and about 23.3 degrees. In some embodiments,Form XI has an XRPD pattern substantially as shown in FIG. 17.

In some embodiments, Form XII has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 5.6, about 11.7, about 13.8,and about 14.5 degrees. In some embodiments, Form XII has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 5.6,about 11.7, about 13.8, about 14.5, about 16.9, about 17.7, and about18.7 degrees. In some embodiments, Form XII has one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 5.6,about 11.7, about 13.8, about 14.5, about 16.9, about 17.7, about 18.7,about 23.5, about 24.6, about 34.3, about 44.2, and 44.6 degrees. Insome embodiments, Form XII has an XRPD pattern substantially as shown inFIG. 18. In some embodiments, Form XII has a DSC thermogramcharacterized by an endothermic peak at a temperature of about 264° C.

In some embodiments, Form XIII has one or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 5.7, about 8.6, about9.8, and about 11.8 degrees. In some embodiments, Form XIII has one ormore characteristic XRPD peaks, in terms of 2-theta, selected from about5.7, about 8.6, about 9.8, about 11.8, about 12.6, about 13.4, about14.1, about 14.8, about 16.6, and about 19.1 degrees. In someembodiments, Form XIII has an XRPD pattern substantially as shown inFIG. 19. In some embodiments, Form XIII has a DSC thermogramcharacterized by an endothermic peak at a temperature of 267° C.

In some embodiments, Form XIV has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 4.0, about 11.2, about 11.9,about 14.1, about 14.8, and about 15.9 degrees. In some embodiments,Form XIV has an XRPD pattern substantially as shown in FIG. 20. In someembodiments, Form XIV has a DSC thermogram characterized by anendothermic peak at a temperature of 267° C.

In some embodiments, Form XV has one or more characteristic XRPD peaks,in terms of 2-theta, selected from about 7.4, about 9.6, about 12.4,about 13.4, and about 15.5 degrees. In some embodiments, Form XV has oneor more characteristic XRPD peaks, in terms of 2-theta, selected fromabout 7.4, about 9.6, about 12.4, about 13.4, about 15.5, about 16.9,about 17.7, about 19.0, about 19.5, about 20.6, and about 22.5 degrees.In some embodiments, Form XV has an XRPD pattern substantially as shownin FIG. 21. In some embodiments, Form XV has a DSC thermogramcharacterized by an endothermic peak at a temperature of about 85° C.,an endothermic peak at a temperature of about 172° C., an exothermicpeak at a temperature of about 192° C., an endothermic peak at atemperature of about 268° C., or a combination thereof.

As used herein, the phrase “solid form” refers to a compound providedherein in either an amorphous state or a crystalline state (“crystallineform” or “crystalline solid” or “crystalline solid form”), whereby acompound provided herein in a crystalline state may optionally includesolvent or water within the crystalline lattice, for example, to form asolvated or hydrated crystalline form. The term “hydrated,” as usedherein, is meant to refer to a crystalline form that includes watermolecules in the crystalline lattice. Example “hydrated” crystallineforms include hemihydrates, monohydrates, dihydrates, and the like.Other hydrated forms such as channel hydrates and the like are alsoincluded within the meaning of the term.

The different crystalline forms of the compound provide herein (e.g.,Compound 1) are characterized by X-ray powder diffraction (XRPD),differential scanning calorimetry (DSC), and/or thermogravimetricanalysis (TGA). An X-ray powder diffraction (XRPD) pattern ofreflections (peaks) is typically considered a fingerprint of aparticular crystalline form. It is well known that the relativeintensities of the XRPD peaks can widely vary depending on, inter alia,the sample preparation technique, crystal size distribution, variousfilters used, the sample mounting procedure, and the particularinstrument employed. In some instances, new peaks may be observed orexisting peaks may disappear depending on the type of instrument or thesettings (for example, whether a Ni filter is used or not). As usedherein, the term “peak” or “characteristic peak” refers to a reflectionhaving a relative height/intensity of at least about 3% of the maximumpeak height/intensity. Moreover, instrument variation and other factorscan affect the 2-theta values. Thus, peak assignments, such as thosereported herein, can vary by plus or minus about 0.2° (2-theta), and theterm “substantially” or “about” as used in the context of XRPD herein ismeant to refer to the above-mentioned variations.

In the same way, temperature readings in connection with DSC, TGA, orother thermal experiments can vary about ±3° C. depending on theinstrument, particular settings, sample preparation, etc. Accordingly, acrystalline form reported herein having a DSC thermogram “substantially”as shown in any of the Figures is understood to accommodate suchvariation.

The term “crystalline form” is meant to refer to a certain latticeconfiguration of a crystalline substance. Different crystalline forms ofthe same substance typically have different crystalline lattices (e.g.,unit cells), typically have different physical properties attributed totheir different crystalline lattices, and in some instances, havedifferent water or solvent content. The different crystalline latticescan be identified by solid state characterization methods such as byX-ray powder diffraction (XRPD). Other characterization methods such asdifferential scanning calorimetry (DSC), thermogravimetric analysis(TGA), dynamic vapor sorption (DVS), and the like further help identifythe crystalline form as well as help determine stability andsolvent/water content.

Different crystalline forms of a particular substance, such as Compound1, can include both anhydrous forms of that substance andsolvated/hydrated forms of that substance, where each of the anhydrousforms and solvated/hydrated forms are distinguished from each other bydifferent XRPD patterns, or other solid state characterization methods,thereby signifying different crystalline lattices. In some instances, asingle crystalline form (e.g., identified by a unique XRPD pattern) canhave variable water or solvent content, where the lattice remainssubstantially unchanged (as does the XRPD pattern) despite thecompositional variation with respect to water and/or solvent.

In some embodiments, the compounds (or hydrates and solvates thereof) ofthe application are prepared in batches referred to as batches, samples,or preparations. The batches, samples, or preparations can include thecompounds provided herein in any of the crystalline or non-crystallineforms described herein, including hydrated and non-hydrated forms, andmixtures thereof.

The compounds disclosed herein can include all isotopes of atomsoccurring within them. Isotopes include those atoms having the sameatomic number but different mass numbers. For example, isotopes ofhydrogen include tritium and deuterium.

In some embodiments, the compounds provided herein (e.g., Compound 1),or salts thereof, or crystalline forms thereof, are substantiallyisolated. The term “substantially isolated” is meant that the compoundor salt is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compound, salts, orcrystalline forms provided herein. Substantial separation can includecompositions containing at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%, or at least about 99% by weight of the compounds,salts, or crystalline forms provided herein.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Processes for Preparation of Compound 1

The present application further provides a process of preparing Compound1, where the process can be suitable for scale up. A process ofpreparing Compound 1 is described in US 2015/0307493, the entirety ofwhich is incorporated herein by reference. In comparison to the processdescribed in US 2015/0307493, the process provided herein has certainadvantages making it suitable for scale up. For example, processprovided herein uses less hazardous reagents while affording high yieldsand good quality products. Further, the process provided herein cangenerate Compound 7 (see below) in situ without isolating of Compound 7,which provides better efficiency on a large scale.

In some embodiments, the process of preparing Compound 1 comprisesreacting Compound 8:

with B1, wherein B1 is a base.

In some embodiments, B1 is an alkali metal hydroxide base such as sodiumhydroxide. The reacting of Compound 8 with B1 can be carried out in asolvent. In some embodiments, the solvent comprises an ether solventsuch as 1,4-dioxane. Ether solvents such as 1,4-dioxane can affordCompound 1 in high yields and good quality. In some embodiments, thereacting of Compound 8 with B1 is carried out at elevated temperature,for example, at a temperature of about 50° C. to about 85° C. (e.g.,about 60° C. to about 80° C. or about 65° C. to about 75° C.). In someembodiments, the temperature is about 70° C. In some embodiments, B1 isprovided in molar excess with respect to the amount of Compound 8. Insome embodiments, about 3 to about 4 or about 3.5 equivalent of B1 isused based on 1 equivalent of Compound 8.

In some embodiments, the process further comprises reacting Compound 7:

with Compound 9:

in the presence of P2 and B2 to form Compound 8, wherein P2 is atransition metal catalyst and B2 is a base.

In some embodiments, P2 is transition metal catalyst such as a palladiumcatalyst. Examples of palladium catalysts include[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂, e.g., Pd(dppf)Cl₂—CH₂Cl₂),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})panadium(Pd-132), Pd(PPh₃)₄, and tetrakis(tri(o-tolyl)phosphine)palladium(0). Insome embodiments, P2 is Pd(dppf)Cl₂. In some embodiments, B2 is analkali metal bicarbonate base such as sodium bicarbonate. In someembodiments, B2 is an alkali metal carbonate base such as K₂CO₃. Thereacting of Compound 7 with Compound 9 can be carried out in a solvent.In some embodiments, the solvent comprises a protic solvent, an ethersolvent, or a mixture thereof. In some embodiments, the solventcomprises water, 1,4-dioxane, or a mixture thereof. In some embodiments,the reacting of Compound 7 with Compound 9 is carried out at elevatedtemperature, for example, at a temperature of about 80° C. to about 100°C. (e.g., about 85° C. to about 95° C.). In some embodiments, thetemperature is about 90° C. In some embodiments, about 1 equivalent ofthe Compound 9 is used based on 1 equivalent of Compound 7 or Compound 6(which has the structure shown below). In some embodiments, P2 isprovided in a sufficiently catalytic amount. For example, about 0.01 toabout 0.05 or about 0.03 equivalent of P2 is used based on 1 equivalentof Compound 7. In some embodiments, B2 is provided in molar excess withrespect to the amount of Compound 9. In some embodiments, about 2 toabout 3 or about 2.5 equivalents of B2 is used based on 1 equivalent ofCompound 9.

In some embodiments, the process further comprises reacting Compound 6:

with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P3 and B3 to form Compound 7, wherein P3 is a transitionmetal catalyst and B3 is a base.

In some embodiments, P3 is a transition metal catalyst such as apalladium catalyst. Examples of palladium catalysts include[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂, e.g., Pd(dppf)Cl₂—CH₂Cl₂),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl}palladium(Pd-132), Pd(PPh₃)₄, and tetrakis(tri(o-tolyl)phosphine)palladium(0). Insome embodiments, P3 is Pd(dppf)Cl₂. In some embodiments, B3 is analkali metal acetate base such as potassium acetate. The reacting ofCompound 6 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) can becarried out in a solvent. In some embodiments, the solvent comprises anether solvent such as 1,4-dioxane. In some embodiments, the reacting ofCompound 6 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) is carriedout at elevated temperature, for example, at a temperature of about 70°C. to about 90° C. (e.g., 75° C. to about 85° C.). In some embodiments,the temperature is about 80° C. In some embodiments, the reagent4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) is providedin molar excess with respect to the amount of Compound 6. In someembodiments, about 2 to about 2.5 equivalents of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) is usedbased on 1 equivalent of Compound 6. In some embodiments, B3 is providedin molar excess with respect to the amount of Compound 6. In someembodiments, about 3 to about 3.5 equivalents of B3 is used based on 1equivalent of Compound 6. In some embodiments, P3 is provided in asufficiently catalytic amount. In some embodiments, about 0.01 to about0.05 or about 0.03 equivalent of P3 is used based on 1 equivalent ofCompound 6.

In some embodiments, the reacting to form Compound 7 and thensubsequently to form Compound 8 is conducted in the same reaction vesselwithout the isolation of Compound 7. When the reacting to form Compound7 and then Compound 8 is conducted in the same reaction vessel (withoutthe isolation of Compound 7), Compound 8 can be formed from Compounds 7and 9 without the addition of P2, e.g., by using P3 (a transition metalcatalyst) in the same reaction vessel to form Compound 7. Alternatively,the coupling reactions to generate Compound 8 from Compound 6 can becarried out in two separate steps, where Compound 7 is isolated and P2is employed in the reaction to generate Compound 8 from Compound 7.

Alternatively, Compound 8 can be prepared by a process comprisingreacting Compound 6 with Compound 15:

in the presence of P4 and B4, wherein P4 is transition metal catalystand B4 is a base.

In some embodiments, P4 is a transition metal catalyst such as apalladium catalyst. Examples of palladium catalysts include4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1),Pd(dppf)Cl₂ (e.g., Pd(dppf)Cl₂—CH₂Cl₂),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl}palladium(Pd-132), Pd(PPh₃)₄, and tetrakis(tri(o-tolyl)phosphine)palladium(0). Insome embodiments, P4 is4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1).In some embodiments, P4 is Pd(dppf)Cl₂ (e.g., Pd(dppf)Cl₂—CH₂Cl₂). Insome embodiments, B4 is a base such as cesium fluoride. In anotherembodiment, B4 is an alkali metal carbonate such as K₂CO₃. The reactingof Compound 6 with Compound 15 can be carried out in a solvent. In someembodiments, the solvent comprises a protic solvent, an ether solvent,or a mixture thereof. In some embodiments, the reacting is carried outin a solvent comprising 1,4-dioxane, water, or a mixture thereof. Insome embodiments, the reacting of Compound 6 with Compound 15 is carriedout at an elevated temperature (e.g., higher than room temperature) suchas at about reflux temperature. In some embodiments, about 1 equivalentof Compound 15 is used based on 1 equivalent of Compound 6. In someembodiments, B4 is provided in molar excess with respect to Compound 6.In some embodiments, about 3 to about 4 or about 3.5 equivalents of B4is used based on 1 equivalent of Compound 6. P4 is typically provided ina sufficiently catalytic amount. In some embodiments, about 0.01 toabout 0.1 or about 0.05 equivalent of P4 is used based on 1 equivalentof Compound 6.

In some embodiments, Compound 15 can be prepared by a process comprisingreacting Compound 9 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P8 and B8, wherein P8 is a transition metal catalyst and B8is a base.

In some embodiments, P8 is a transition metal catalyst such as apalladium catalyst. Examples of palladium catalysts includetris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃,4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1),Pd(dppf)Cl₂ (e.g., Pd(dppf)Cl₂—CH₂Cl₂),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl}palladium(Pd-132), Pd(PPh₃)₄, and tetrakis(tri(o-tolyl)phosphine)palladium(0). Insome embodiments, P8 is tris(dibenzylideneacetone)dipalladium(0)(Pd₂(dba)₃ (e.g., wheredicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (Xphos) can beadded as a ligand). In some embodiments, B8 is an alkali metal acetatebase such as potassium acetate. The reacting of Compound 9 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) can becarried out in a solvent. In some embodiments, the solvent comprises anether solvent such as 1,4-dioxane. In some embodiments, the reacting ofCompound 9 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) is carriedout at a temperature of about 75° C. to about 95° C. In someembodiments, the temperature is about 80° C. to about 90° C. or about80° C. to about 85° C. In some embodiments, about 2 equivalent of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) is usedbased on 1 equivalent of Compound 9. In some embodiments, B8 is providedin molar excess with respect to Compound 9. In some embodiments, about 2to about 3 of B8 is used based on 1 equivalent of Compound 9. P8 istypically provided in a sufficiently catalytic amount. In someembodiments, about 0.01 to about 0.1 or about 0.025 equivalent of P8 isused based on 1 equivalent of Compound 9.

In some embodiments, Compound 6 can be prepared according to theprocedures in US2015/0307493, which is incorporated herein by referencein its entirety.

In some embodiments, Compound 6 is prepared by a process comprisingreacting Compound 5:

with a methylating agent and B5, wherein B5 is a base. In someembodiments, the methylating agent is methyl iodide (MeI), dimethylsulfate, dimethyl carbonate, or tetramethylammonium chloride. In someembodiments, the methylating agent is methyl iodide. In someembodiments, B5 is an alkali metal carbonate base such as potassiumcarbonate (K₂CO₃). In some embodiments, the reacting of Compound 5 withthe methylating agent is carried out in a solvent comprising, forexample, an aprotic solvent such as N′N-dimethylformamide (DMF). In someembodiments, the reacting of Compound 5 with the methylating agent iscarried out at a temperature of about 10° C. to about 20° C. or about15° C. to about 20° C.

In some embodiments, Compound 5 is prepared by a process comprisingreacting Compound 4:

with 2-bromo-2-methylpropanoyl bromide and B6, wherein B6 is a base. Insome embodiments, B6 is an alkali metal carbonate such potassiumcarbonate (K₂CO₃). The reacting of Compound 4 with2-bromo-2-methylpropanoyl bromide can be conducted in the presence of asolvent. For example, the solvent comprises acetonitrile, water, or amixture thereof. The reacting of Compound 4 with2-bromo-2-methylpropanoyl bromide can be carried out at elevatedtemperature, for example, at a temperature of about 60° C. to about 90°C. In some embodiments, the temperature is about 75° C.

In some embodiments, Compound 4 is prepared by a process comprisingreacting Compound 3:

with a reducing agent. In some embodiments, the reducing agent is sodiumhydrosulfite or H₂/Raney Ni. The reacting of Compound 3 with thereducing agent can be conducted in the presence of a solvent. In someembodiments, the solvent comprises a protic solvent (e.g., water andmethanol), an ether solvent (tetrahydrofuran), or a mixture thereof. Insome embodiments, the reacting of Compound 3 and sodium hydrosulfite iscarried out in water, tetrahydrofuran, or a mixture thereof. In someembodiments, the reacting of Compound 3 with H₂/Raney Ni is carried outin methanol. In some embodiments, the reacting of Compound 3 with thereducing agent is carried out at room temperature. In some embodiments,sodium hydrosulfite is used in combination with sodium bicarbonate. Thereacting of Compound 3 with sodium hydrosulfite and sodium bicarbonatecan produce Compound 4 under mild process conditions as compared toH₂/Raney Ni, which can be hazardous on a large scale.

In some embodiments, Compound 3 is prepared by a process comprisingreacting Compound 2:

with N-bromosuccinimide (NBS). The use of NBS can provide high yieldsand good quality product on a large scale, e.g., on a kilo gram scale.In some embodiments, the reacting is carried out in a solvent comprisingan aprotic solvent such as N,N-dimethylformamide (DMF). In someembodiments, the reacting is carried out at room temperature.

In some embodiments, Compound 2 is prepared by a process comprisingreacting Compound 1a:

with nitric acid and acetic acid. In some embodiments, the reacting iscarried out at a temperature of about 60° C. to about 90° C. or about75° C. to about 80° C.

In some embodiments, Compound 9 can be prepared according to theprocedures in US2015/0307493 and WO2013/097601, each of which isincorporated herein by reference in its entirety.

In some embodiments, Compound 9 is prepared by a process comprisingreacting Compound 14:

with methyl iodide and sodium hydride. In some embodiments, the reactingis carried out in a solvent comprising an aprotic solvent such asN′N-dimethylformamide (DMF).

In some embodiments, Compound 14 is prepared by a process comprisingreacting Compound 13:

with an acid. In some embodiments, the acid is a strong aqueous acidsuch as HCl. In some embodiments, the reacting is carried out in asolvent comprising an ether solvent such as 1,4-dixoane.

In some embodiments, Compound 13 is prepared by a process comprisingreacting Compound 12:

with p-toluenesulfonyl chloride (p-TsCl) and sodium hydride (NaH). Insome embodiments, the reacting is carried out in a solvent comprising anaprotic solvent such as N′N-dimethylformamide (DMF).

In some embodiments, Compound 12 is prepared by a process comprisingreacting Compound 11:

with iron (Fe) and acetic acid (HOAc). In some embodiments, the reactingis carried out in a solvent comprising an ether solvent such astetrahydrofuran (THF). The combination of iron and acetic acid can beemployed as a reducing agent and can be a safer alternative to reducingagent such as H₂/Raney Ni, which can be hazardous on a large scale.

In some embodiments, Compound 11 is prepared by a process comprisingreacting Compound 10:

with 1,1-diethoxy-N,N-dimethylmethanamine with B7, wherein B7 is a base.In some embodiments, B7 is an alkali metal alkoxide such lithiummethanolate. In some embodiments, the reacting is carried out in asolvent comprising an aprotic solvent such as N′N-dimethylformamide(DMF).

In some embodiments, the process of preparing Compound 6 comprises:

(i) reacting Compound 1a with nitric acid and acetic acid to formCompound 2;

(ii) reacting Compound 2 with N-bromosuccinimide (NBS) to form Compound3;

(iii) reacting Compound 3 with a reducing agent to form Compound 4;

(iv) reacting Compound 4 with 2-bromo-2-methylpropanoyl bromide and B6to form Compound 5; and

(v) reacting Compound 5 with a methylating agent and B5 to form Compound6.

In some embodiments, the process of preparing Compound 9 comprises:

(i) reacting Compound 10 with 1,1-diethoxy-N,N-dimethylmethanamine withB7 to form Compound 11;

(ii) reacting Compound 11 with iron (Fe) and acetic acid (HOAc) to formCompound 12;

(iii) reacting Compound 12 with p-toluenesulfonyl chloride (p-TsCl) andsodium hydride (NaH) to form Compound 13;

(iv) reacting Compound 13 with an acid to form Compound 14; and

(v) reacting Compound 14 with methyl iodide and sodium hydride to formCompound 9.

In some embodiments, the process of preparing Compound 1, or a saltthereof, comprises:

(i) reacting Compound 6 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P3 and B3 to form Compound 7;

(ii) reacting Compound 7 with Compound 9 in the presence of P2 and B2 toform Compound 8; and

(iii) reacting Compound 8 with B1 to form Compound 1, or a salt thereof.

In some embodiments, the process of preparing Compound 1, or a saltthereof, comprises:

(i) reacting Compound 6 with Compound 15 in the presence of P4 and B4 toform Compound 8; and

(ii) reacting Compound 8 with B1 to form Compound 1, or a salt thereof.

In some embodiments, the process of preparing Compound 1, or a saltthereof, comprises:

(i) reacting Compound 9 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P8 and B8 to form Compound 15;

(ii) reacting Compound 6 with Compound 15 in the presence of P4 and B4to form Compound 8; and

(iii) reacting Compound 8 with B1 to form Compound 1, or a salt thereof.

In some embodiments, the process of preparing Compound 1 comprises:

(i) reacting Compound 1a with nitric acid and acetic acid to formCompound 2;

(ii) reacting Compound 2 with N-bromosuccinimide (NBS) to form Compound3;

(iii) reacting Compound 3 with a reducing agent to form Compound 4;

(iv) reacting Compound 4 with 2-bromo-2-methylpropanoyl bromide and B6to form Compound 5;

(v) reacting Compound 5 with a methylating agent and B5 to form Compound6;

(vi) reacting Compound 6 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P3 and B3 to form Compound 7; (vii) reacting Compound 7 withCompound 9 in the presence of P2 and B2 to form Compound 8; and (viii)reacting Compound 8 with B1 to form Compound 1.

In some embodiments, the process of preparing Compound 1 comprises:

(i) reacting Compound 1a with nitric acid and acetic acid to formCompound 2;

(ii) reacting Compound 2 with N-bromosuccinimide (NBS) to form Compound3;

(iii) reacting Compound 3 with a reducing agent to form Compound 4;

(iv) reacting Compound 4 with 2-bromo-2-methylpropanoyl bromide and B6to form Compound 5;

(v) reacting Compound 5 with a methylating agent and B5 to form Compound6;

(vi) reacting Compound 6 with Compound 15 in the presence of P4 and B4to form Compound 8; and

(vii) reacting Compound 8 with B1 to form Compound 1.

In some embodiments, the process of preparing Compound 1 comprises:

(i) reacting Compound 10 with 1,1-diethoxy-N,N-dimethylmethanamine withB7 to form Compound 11;

(ii) reacting Compound 11 with iron (Fe) and acetic acid (HOAc) to formCompound 12;

(iii) reacting Compound 12 with p-toluenesulfonyl chloride (p-TsCl) andsodium hydride (NaH) to form Compound 13;

(iv) reacting Compound 13 with an acid to form Compound 14;

(v) reacting Compound 14 with methyl iodide and sodium hydride to formCompound 9;

(vi) reacting Compound 7 with Compound 9 in the presence of P2 and B2 toform Compound 8; and

(vii) reacting Compound 8 with B1 to form Compound 1.

In some embodiments, the process of preparing Compound 1 comprises:

(i) reacting Compound 10 with 1,1-diethoxy-N,N-dimethylmethanamine withB7 to form Compound 11;

(ii) reacting Compound 11 with iron (Fe) and acetic acid (HOAc) to formCompound 12;

(iii) reacting Compound 12 with p-toluenesulfonyl chloride (p-TsCl) andsodium hydride (NaH) to form Compound 13;

(iv) reacting Compound 13 with an acid to form Compound 14;

(v) reacting Compound 14 with methyl iodide and sodium hydride to formCompound 9;

(vi) reacting Compound 9 with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P8 and B8 to form Compound 15;

(vii) reacting Compound 6 with Compound 15 in the presence of P4 and B4to form Compound 8; and

(viii) reacting Compound 8 with B1 to form Compound 1.

In some embodiments, provided herein is a compound which is

or a salt thereof.

In some embodiments, provided herein is a process of reacting Compound 6with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of P3 and B3 to form Compound 7.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

In some embodiments, a solution of Compound 1 at elevated temperature asdescribed herein refers to a solution at a temperature that is aboveroom temperature. For example, solution of Compound 1 at elevatedtemperature would have a temperature above about room temperature, e.g.,above about 20° C., above about 30° C., above about 40° C., above about50° C., above about 60° C., above about 70° C., above about 80° C.,above about 90° C., or above about 100° C.

In some embodiments, concentrating a solution as described herein refersto a solution where its volume is reduced by letting the solventevaporate, by heating the solution, by subjecting the solution toreduced pressure, or any combination thereof.

As used herein, the phrase “alkali metal bicarbonate base,” employedalone or in combination with other terms, refers to a base havingformula M(HCO₃), wherein M refers to an alkali metal (e.g. lithium,sodium, or potassium). Example alkali metal bicarbonate bases include,but are not limited to, lithium bicarbonate, sodium bicarbonate, andpotassium bicarbonate.

As used herein, the phrase “alkali metal carbonate base,” employed aloneor in combination with other terms, refers to a base having formulaM₂CO₃, wherein M refers to an alkali metal (e.g. lithium, sodium, orpotassium). Example alkali metal carbonate bases include, but are notlimited to lithium carbonate, sodium carbonate, and potassium carbonate.

As used herein, the phrase “alkali metal hydroxide base,” employed aloneor in combination with other terms, refers to a base having formula MOH,wherein M refers to an alkali metal (e.g. lithium, sodium, orpotassium). Example alkali metal hydroxide bases include, but are notlimited to lithium hydroxide, sodium hydroxide, and potassium hydroxide.

As used herein, the phrase “alkali metal acetate base,” employed aloneor in combination with other terms, refers to a base having formulaM(OC(O)CH₃), wherein M refers to an alkali metal (e.g. lithium, sodium,or potassium). Example alkali metal acetate bases include, but are notlimited to lithium acetate, sodium acetate, and potassium acetate.

As used herein, the phrase “transition metal catalyst” refers to a metalcatalyst (e.g., palladium or nickel catalyst) suitable to catalyze acarbon-carbon coupling reaction. Example transition metal catalystsinclude, but are not limited to, PdCl₂(PPh₃)₂, Pd(PPh₃)₄,dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})ppalladium(Pd-132), NiCl₂(dppf), and NiCl₂(dppp), where (dppf) refers to1,1′-bis(diphenylphosphino)ferrocene and (dppp) refers to1,3-bis(diphenylphosphino)propane.

Example palladium catalysts include but are not limited to PdCl₂(PPh₃)₂,Pd(PPh₃)₄,dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl}Vanadium(Pd-132), palladium on carbon, PdCl₂, Pd(OAc)₂, PdCl₂(MeCN)₂,tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃,4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1),Pd(dppf)Cl₂ (e.g., Pd(dppf)Cl₂—CH₂Cl₂), andtetrakis(tri(o-tolyl)phosphine)palladium(0).

As used herein, the term “reacting,” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation. In some embodiments, thereacting involves two reagents, wherein one or more equivalents ofsecond reagent are used with respect to the first reagent. The reactingsteps of the processes described herein can be conducted for a time andunder conditions suitable for preparing the identified product.

In some embodiments, anti-solvent as described herein refers to asolvent where Compound 1 is less soluble relative to another solvent orsolvent mixture in the solution. For example, anti-solvent can includebut not limited to benzene, cyclohexane, pentane, hexane, heptane (e.g.,n-heptane), toluene, cycloheptane, methylcyclohexane, heptane,ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, ornaphthalene.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane (methylene chloride), tetrachloroethylene,trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane,1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene,1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene,1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene,fluorobenzene, mixtures thereof and the like.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether,ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethylene glycol dimethyl ether (diglyme), diethylene glycol diethylether, triethylene glycol dimethyl ether, anisole, tert-butyl methylether, mixtures thereof and the like.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tent-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, tent-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

Methods of Use

Compound 1, or a salt thereof, is a BET protein inhibitor and thus, isuseful in treating diseases and disorders associated with activity ofBET proteins. For the uses described herein, any forms of Compound 1,including any of the embodiments described herein, may be used.

Compound 1 can inhibit one or more of BET proteins BRD2, BRD3, BRD4, andBRD-t. In some embodiments, Compound 1 selectively inhibits one or moreBET proteins over another.

“Selective” means that the compound binds to or inhibits a BET proteinwith greater affinity or potency, respectively, compared to a reference,such as another BET protein. For example, the compound can be selectivefor BRD2 over BRD3, BRD4 and BRD-t, selective for BRD3 over BRD2, BRD4and BRD-t, selective for BRD4 over BRD2, BRD3 and BRD-t, or selectivefor BRD-t over BRD2, BRD3 and BRD4. In some embodiments, the compoundinhibits two or more of the BET proteins, or all of the BET proteins. Ingeneral, selectivity can be at least about 5-fold, at least about10-fold, at least about 20-fold, at least about 50-fold, at least about100-fold, at least about 200-fold, at least about 500-fold or at leastabout 1000-fold.

Compound 1 is therefore useful for treating BET protein mediateddisorders. The term “BET protein mediated disorder” or “BET-mediateddisorder” refers to any disorder, disease or condition in which one ormore of the BET proteins, such as BRD2, BRD3, BRD4 and/or BRD-t, or amutant thereof, plays a role, or where the disease or condition isassociated with expression or activity of one or more of the BETproteins. Compound 1, as an inhibitor of BET proteins, can therefore beused to treat or lessen the severity of diseases and conditions whereBET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t, or a mutantthereof, are known to play a role.

Diseases and conditions treatable using Compound 1 include, but are notlimited to, cancer and other proliferative disorders, autoimmunedisease, chronic inflammatory diseases, acute inflammatory diseases,sepsis, and viral infection. The diseases can be treated byadministering to an individual (e.g., a patient) in need of thetreatment a therapeutically effective amount or dose of Compound 1, orany of the embodiments thereof, or a pharmaceutical composition thereof.The present disclosure also provides a solid form of Compound 1, or anyof the embodiments thereof, or a pharmaceutical composition comprisingthe solid form, for use in treating a BET-mediated disease or disorder.Also provided is the use of a solid form of Compound 1, or any of theembodiments thereof, or a pharmaceutical composition comprising thesolid form, in the manufacture of a medicament for treating aBET-mediated disease or disorder.

Diseases that can be treated with Compound 1 include cancers. Thecancers can include, but are not limited to, adrenal cancer, acinic cellcarcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma,acute eosinophilic leukemia, acute erythroid leukemia, acutelymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocyticleukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cysticcarcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamouscarcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adultT-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-relatedlymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma,ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroidcancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma,angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cellchronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-celllymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer,blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma,breast cancer, brain cancer, carcinoma, carcinoma in situ,carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma,chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcomaof the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervicalcancer, colorectal cancer, Degos disease, desmoplastic small round celltumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelialtumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm,endodermal sinus tumor, enteropathy-associated T-cell lymphoma,esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicularlymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinalcancer, germ cell tumor, gestational choriocarcinoma, giant cellfibroblastoma, giant cell tumor of the bone, glial tumor, glioblastomamultiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma,granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastriccancer, hairy cell leukemia, hemangioblastoma, head and neck cancer,hemangiopericytoma, hematological malignancy, hepatoblastoma,hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer,laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia,leydig cell tumor, liposarcoma, lung cancer, lymphangioma,lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocyticleukemia, acute myelogenous leukemia, chronic lymphocytic leukemia,liver cancer, small cell lung cancer, non-small cell lung cancer, MALTlymphoma, malignant fibrous histiocytoma, malignant peripheral nervesheath tumor, malignant triton tumor, mantle cell lymphoma, marginalzone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor,medullary carcinoma of the breast, medullary thyroid cancer,medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma,metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor,multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoidliposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma,neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer,oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheathmeningioma, optic nerve tumor, oral cancer, osteosarcoma, ovariancancer, Pancoast tumor, papillary thyroid cancer, paraganglioma,pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitarytumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma,primary central nervous system lymphoma, primary effusion lymphoma,primary peritoneal cancer, prostate cancer, pancreatic cancer,pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renalmedullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma,Richter's transformation, rectal cancer, sarcoma, Schwannomatosis,seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signetring cell carcinoma, skin cancer, small blue round cell tumors, smallcell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinaltumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovialsarcoma, Sezary's disease, small intestine cancer, squamous carcinoma,stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroidcancer, transitional cell carcinoma, throat cancer, urachal cancer,urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer,verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginalcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms'tumor. In some embodiments, the cancer can be adenocarcinoma, adultT-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breastcancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer,colorectal cancer, esophageal cancer, gastrointestinal cancer,glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer,head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma,intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lungcancer, lymphoma, liver cancer, small cell lung cancer, non-small celllung cancer, mesothelioma, multiple myeloma, acute myeloid leukemia(AML), diffuse large B-cell lymphoma (DLBCL), ocular cancer, optic nervetumor, oral cancer, ovarian cancer, pituitary tumor, primary centralnervous system lymphoma, prostate cancer, pancreatic cancer, pharyngealcancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer,spinal tumor, small intestine cancer, stomach cancer, T-cell lymphoma,testicular cancer, thyroid cancer, throat cancer, urogenital cancer,urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.

In some embodiments, the cancer is a hematological cancer.

In some embodiments, the cancer is multiple myeloma, acute myeloidleukemia (AML), or diffuse large B-cell lymphoma (DLBCL).

The diseases treatable using Compound 1 also include MYC dependentcancers wherein the cancer is associated with at least one of myc RNAexpression or MYC protein expression. A patient can be identified forsuch treatment by determining myc RNA expression or MYC proteinexpression in the cancerous tissue or cells.

Diseases that can be treated with Compound 1 also include non-cancerousproliferative disorders. Examples of proliferative disorders that can betreated include, but are not limited to, benign soft tissue tumors, bonetumors, brain and spinal tumors, eyelid and orbital tumors, granuloma,lipoma, meningioma, multiple endocrine neoplasia, nasal polyps,pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, and juvenile polyposis syndrome.

The diseases and conditions that can be treated with Compound 1 alsoinclude chronic autoimmune and inflammatory conditions. Examples ofautoimmune and inflammatory conditions that can be treated includeacute, hyperacute or chronic rejection of transplanted organs, acutegout, acute inflammatory responses (such as acute respiratory distresssyndrome and ischemia/reperfusion injury), Addison's disease,agammaglobulinemia, allergic rhinitis, allergy, alopecia, Alzheimer'sdisease, appendicitis, atherosclerosis, asthma, osteoarthritis, juvenilearthritis, psoriatic arthritis, rheumatoid arthriti, satopic dermatitis,autoimmune alopecia, autoimmune hemolytic and thrombocytopenic states,autoimmune hypopituitarism, autoimmune polyglandular disease, Behcet'sdisease, bullous skin diseases, cholecystitis, chronic idiopathicthrombocytopenic purpura, chronic obstructive pulmonary disease (COPD),cirrhosis, degenerative joint disease, depression, dermatitis,dermatomyositis, eczema, enteritis, encephalitis, gastritisglomerulonephritis, giant cell arteritis, Goodpasture's syndrome,Guillain-Barre syndrome, gingivitis, Graves' disease, Hashimoto'sthyroiditis, hepatitis, hypophysitis, inflammatory bowel disease(Crohn's disease and ulcerative colitis), inflammatory pelvic disease,irritable bowel syndrome, Kawasaki disease, LPS-induced endotoxic shock,meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosisfungoides, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson'sdisease, pericarditis, pernicious anemia, pneumonitis, primary biliarysclerosing cholangitis, polyarteritis nodosa, psoriasis, retinitis,scleritis, scleracierma, scleroderma, sinusitis, Sjogren's disease,sepsis, septic shock, sunburn, systemic lupus erythematosus, tissuegraft rejection, thyroiditis, type I diabetes, Takayasu's arteritis,urethritis, uveitis, vasculitis, vasculitis including giant cellarteritis, vasculitis with organ involvement such as glomerulonephritis,vitiligo, Waldenstrom macroglobulinemia and Wegener's granulomatosis.

The diseases and conditions that can be treated with Compound 1 alsoinclude diseases and conditions which involve inflammatory responses toinfections with bacteria, viruses, fungi, parasites or their toxins,such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemicinflammatory response syndrome (SIRS), multi-organ dysfunction syndrome,toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, fulminant hepatitis, burns,acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, malaria, SIRS associatedwith viral infections such as influenza, herpes zoster, herpes simplexand coronavirus.

Other diseases that can be treated with Compound 1 include viralinfections. Examples of viral infections that can be treated includeEpstein-Barr virus, hepatitis B virus, hepatitis C virus, herpes virus,human immunodeficiency virus, human papilloma virus, adenovirus,poxvirus and other episome-based DNA viruses. Compound 1 can thereforebe used to treat disease and conditions such as herpes simplexinfections and reactivations, cold sores, herpes zoster infections andreactivations, chickenpox, shingles, human papilloma virus, cervicalneoplasia, adenovirus infections, including acute respiratory disease,and poxvirus infections such as cowpox and smallpox and African swinefever virus. In some embodiments, Compound 1 can be used in thetreatment of human papilloma virus infections of skin or cervicalepithelia.

The diseases and conditions that can be treated with Compound 1 alsoinclude conditions that are associated with ischaemia-reperfusioninjury. Examples of such conditions include, but are not limited toconditions such as myocardial infarction, cerebrovascular ischaemia(stroke), acute coronary syndromes, renal reperfusion injury, organtransplantation, coronary artery bypass grafting, cardio-pulmonarybypass procedures and pulmonary, renal, hepatic, gastrointestinal orperipheral limb embolism.

Compound 1 is also useful in the treatment of disorders of lipidmetabolism via the regulation of APO-A1 such as hypercholesterolemia,atherosclerosis and Alzheimer's disease.

Compound 1 is also useful in the treatment of fibrotic conditions suchas idiopathic pulmonary fibrosis, renal fibrosis, post-operativestricture, keloid formation, scleroderma and cardiac fibrosis.

Compound 1 can also be used to treat ophthamological indications such asdry eye.

Compound 1 can also be used to treat heart disease such as heartfailure.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a BET protein with Compound 1 (e.g., a solid formof Compound 1 such as a crystalline solid form) includes theadministration of Compound 1 to an individual or patient, such as ahuman, having a BET protein, as well as, for example, introducing solidform of a compound provided herein into a sample containing a cellularor purified preparation containing the BET protein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

Compound 1 can be used in combination treatments where Compound 1 isadministered in conjunction with other treatments such as theadministration of one or more additional therapeutic agents. Theadditional therapeutic agents are typically those which are normallyused to treat the particular condition to be treated. The additionaltherapeutic agents can include, e.g., chemotherapeutics,anti-inflammatory agents, steroids, immunosuppressants, as well asBcr-Abl, Flt-3, RAF, FAK, and JAK kinase inhibitors for treatment of BETprotein-associated diseases, disorders or conditions. The one or moreadditional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

In some embodiments, Compound 1 can be used in combination with atherapeutic agent that targets an epigenetic regulator. Examples ofepigenetic regulators include the histone lysine methyltransferases,histone arginine methyl transferases, histone demethylases, histonedeacetylases, histone acetylases, and DNA methyltransferases. Histonedeacetylase inhibitors include, e.g., vorinostat.

For treating cancer and other proliferative diseases, Compound 1 can beused in combination with chemotherapeutic agents, or otheranti-proliferative agents. Compound 1 can also be used in combinationwith medical therapy such as surgery or radiotherapy, e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes.Examples of suitable chemotherapeutic agents include any of: abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

For treating cancer and other proliferative diseases, Compound 1 can beused in combination with ruxolitinib.

Compound 1 can be used in combination with one or more immune checkpointinhibitors. Exemplary immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD27, CD28, CD40, CD122,CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments,the immune checkpoint molecule is a stimulatory checkpoint moleculeselected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In someembodiments, the immune checkpoint molecule is an inhibitory checkpointmolecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3,PD-1, TIM3, and VISTA. In some embodiments, the compounds providedherein can be used in combination with one or more agents selected fromKIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L2 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compound 1 can be used in combination with one or more agents for thetreatment of diseases such as cancer. In some embodiments, the agent isan alkylating agent, a proteasome inhibitor, a corticosteroid, or animmunomodulatory agent. Examples of an alkylating agent includecyclophosphamide (CY), melphalan (MEL), and bendamustine. In someembodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). For treating autoimmune or inflammatory conditions,Compound 1 can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, Compound 1 can beadministered in combination with an immune suppressant such asfluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon),or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, Compound 1 can beadministered in combination with one or more additional agents selectedfrom Dehydrex™ (Holles Labs), Civamide (Opko), sodium hyaluronate(Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, SirionTherapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, Compound 1 can be administered in combination withone or more agents selected from an antibiotic, antiviral, antifungal,anesthetic, anti-inflammatory agents including steroidal andnon-steroidal anti-inflammatories, and anti-allergic agents. Examples ofsuitable medicaments include aminoglycosides such as amikacin,gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin;fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin,trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine;sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin;colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and itsderivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins;amphotericins; fluconazole; flucytosine; natamycin; miconazole;ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac;suprofen; cromolyn; lodoxamide; levocabastin; naphazoline; antazoline;pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

In some embodiments, Compound 1 is administered in combination with aJAK kinase inhibitor (e.g., ruxolitinib, tofacitinib, baricitinib,CYT387, GLPG0634, lestaurtinib, pacritinib, TG101348, or aJAK1-selective inhibitor), a Pim kinase inhibitor (including inhibitorsof one or more of PIM1, PIM2, and PIM3), a PI3 kinase inhibitorincluding PI3K-delta selective and broad spectrum PI3K inhibitors, anMEK inhibitor, a cyclin dependent kinase inhibitor, a b-RAF inhibitor,an mTOR inhibitor, a proteasome inhibitor (e.g., bortezomib,carfilzomib), an HDAC-inhibitor (e.g., panobinostat, vorinostat), a DNAmethyl transferase inhibitor, dexamethasone, melphalan, or animmunomodulator (e.g., lenolidomide, pomalidomide).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, Compound 1 (e.g., a solid form ofCompound 1 such as a crystalline solid form) can be administered aspharmaceutical compositions. These compositions can be prepared in amanner well known in the pharmaceutical art, and can be administered bya variety of routes, depending upon whether local or systemic treatmentis desired and upon the area to be treated.

Administration may be topical (including transdermal, epidermal,ophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal orintranasal), oral or parenteral. Parenteral administration includesintravenous, intraarterial, subcutaneous, intraperitoneal intramuscularor injection or infusion; or intracranial, e.g., intrathecal orintraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This application also includes pharmaceutical compositions whichcontain, as the active ingredient, Compound 1 or a pharmaceuticallyacceptable salt thereof, in combination with one or morepharmaceutically acceptable carriers (excipients). In some embodiments,the composition is suitable for topical administration. In making thecompositions of described herein, the active ingredient is typicallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier in the form of, for example, a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, Compound 1 can be milled to provide theappropriate particle size prior to combining with the other ingredients.If Compound 1 is substantially insoluble, it can be milled to a particlesize of less than 200 mesh. If Compound 1 is substantially watersoluble, the particle size can be adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g., about 40mesh.

Compound 1 may be milled using known milling procedures such as wetmilling to obtain a particle size appropriate for tablet formation andfor other formulation types. Finely divided (nanoparticulate)preparations of Compound 1 can be prepared by processes known in theart, e.g., see International App. No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions provided herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form containing adesired amount of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of provided herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above.

The tablets or pills described herein can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the Compound 1 and compositions providedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. The topical formulationscan be suitably packaged in tubes of, for example, 100 g which areoptionally associated with instructions for the treatment of the selectindication, e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage Compound 1 can vary according to, for example,the particular use for which the treatment is made, the manner ofadministration of the compound, the health and condition of the patient,and the judgment of the prescribing physician. The proportion orconcentration of a compound provided herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. The dosage is likely to depend on such variables asthe type and extent of progression of the disease or disorder, theoverall health status of the particular patient, the relative biologicalefficacy of the compound selected, formulation of the excipient, and itsroute of administration. Effective doses can be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

The compositions provided herein can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more BET proteins as described below.

EXAMPLES Example 1. Synthesis of2,2,4-Trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1)

Synthesis of intermediate Compound 5 was carried out according to Scheme1.

Step 1a. 4-(Methylsulfonyl)-2-nitrophenol (Compound 2)

Nitric acid (69%, 4.2 mL, 70 mmol, 1.2 equiv) was added over one minuteto a stirred solution of 4-(methylsulfonyl)-phenol (Compound 1a, 10 g,58.1 mmol) in acetic acid (HOAc, 91 mL) at room temperature. Thereaction was heated to 70° C., when an exotherm was observed. Thereaction mixture was stirred at 75-80° C. for three hours. Nitric acid(69%, 0.3 mL, 5.0 mmol, 0.086 equiv) was added and the mixture wasstirred for an additional one hour. The reaction mixture was cooled to15° C. and water (230 mL) was added. After stirring for 30 minutes, theresulting solids were collected by filtration, rinsed with water (2×45mL), and dried under vacuum at 45° C. for 5 hours to give the crudedesired product, 4-(methylsulfonyl)-2-nitrophenol (Compound 2, 11.0 g).The crude Compound 2 was then dissolved in tetrahydrofuran (THF, 110 mL)at 55° C. and warm water (45° C., 275 mL) was added slowly. The solutionwas gradually cooled to room temperature and stirred at room temperatureovernight before being further cooled to 9° C. and stirred at 9° C. forone hour. The solids were collected by filtration and dried under vacuumat 50° C. overnight to give 4-(methylsulfonyl)-2-nitrophenol (Compound2, 10.15 g, 12.6 g theoretical, 80.6% yield) as a yellow powder.Compound 2: LCMS calculated for C₇H₈NO₄S (M+H)⁺: 218.0, Found: 218.1; ¹HNMR (300 MHz, DMSO-d₆) δ 12.20 (br s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.00(dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 3.22 (s, 3H) ppm.

Step 2a. 2-Bromo-4-(methylsulfonyl)-6-nitrophenol (Compound 3)

N-Bromosuccinimide (NBS, 680 g, 3.82 moles, 1.0 equiv) was added at 0°C. to a solution of 4-(methylsulfonyl)-2-nitro-phenol (Compound 2, 825g, 3.8 moles) in DMF (5.9 L). The cooling bath was removed after 10minutes and the reaction mixture was stirred at room temperature for twohours. When LCMS indicated the reaction was complete, water (5.9 L) wasadded and the mixture was stirred at room temperature for one hour. Thesolids were filtered, washed with water (3×2.5 L) and dried under vacuumat 45° C. overnight to give 2-bromo-4-(methylsulfonyl)-6-nitrophenol(Compound 3, 1085 g, 1131.1 g theoretical, 95.9% yield) as yellowpowder, which was used in the subsequent reaction without furtherpurification. Compound 3: LCMS calculated for C₇H₆BrNO₅S (M−H)⁻: 293.9,Found: 294.0; ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (d, J=2.0 Hz, 1H), 8.31(d, J=2.0 Hz, 1H), 3.27 (s, 3H) ppm.

Step 3a. 2-Amino-6-bromo-4-(methylsulfonyl)phenol (Compound 4)

Sodium bicarbonate (NaHCO₃, 2.6 kg, 30.95 moles, 8.8 equiv) was addedportion wise over one hour to a solution of2-bromo-4-(methylsulfonyl)-6-nitrophenol (Compound 3, 1037 g, 3.5 moles)and sodium hydrosulfite (Na₂S₂O₄, 85% technical grade, 3.15 kg, 15.4moles, 4.4 equiv) in a 1 to 1 mixture of tetrahydrofuran (THF, 10 L) andwater (10 L). The resulting reaction mixture was stirred at roomtemperature for two hours. When LCMS indicated the reaction wascomplete, the reaction mixture was extracted with ethyl acetate (EtOAc,2×10 L). The combined organic layers were concentrated under reducedpressure. The residue was dissolved in ethyl acetate (EtOAc, 13 L) andthe insoluble material was removed by filtration. The filtrate wasevaporated under reduced pressure to afford crude2-amino-6-bromo-4-(methylsulfonyl)phenol (Compound 4, 736.5 g, 931.4 gtheoretical, 79% yield) as beige powder, which was used in thesubsequent reaction without further purification. Compound 4: LCMScalculated for C₇H₈BrNO₃S (M+H)⁺: 265.9, Found: 266.1; ¹H NMR (300 MHz,DMSO-d₆) δ 7.15 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.8 (br s,2H), 3.4 (br s, 1H), 3.09 (s, 3H) ppm.

Step 4a.8-Bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 5)

A solution of potassium carbonate (K₂CO₃, 842 g, 6.1 moles, 4.15 equiv)in water (2.8 L) was added to a solution of2-amino-6-bromo-4-(methylsulfonyl)phenol (Compound 4, 391 g, 1.47 moles)in acetonitrile (8 L) at room temperature. 2-Bromo-2-methylpropanoylbromide (466 mL, 864 g, 3.76 moles, 2.56 equiv) was then added to thereaction mixture over 20 minutes at room temperature and the resultingreaction mixture was stirred at room temperature overnight. When LCMSindicated the corresponding ring-open intermediate had formed, thereaction mixture was heated to 75° C. for 6 hours. The reaction mixturewas concentrated under reduced pressure to half volume. Water (4 L) and1 N aqueous hydrochloric acid (HCl, 2.24 L) were added and the mixturewas stirred for 15 minutes. The solids were collected by filtration,washed with water (1.2 L), and dried under vacuum at 50° C. overnight togive the crude desired product (Compound 5, 404 g). The crude productwas then triturated with a 5 to 1 mixture of heptanes and MTBE (1.2 L)at room temperature for three hours. The solids were collected byfiltration, washed with heptanes (1 L), and dried under vacuum to afford8-bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 5, 401 g, 491.3 g theoretical, 81.6% yield, 98% purity) asyellow to brown powders. Compound 5: LCMS calculated for C₁₁H₁₂BrNO₄S(M+H)⁺: 334.0, Found: 333.9; ¹H NMR (300 MHz, DMSO-d₆) δ 11.10 (s, 1H),7.74 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 3.22 (s, 3H), 1.46 (s,6H) ppm.

Step 5a.8-Bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 6)

A 200 L glass reactor was assembled with an overhead stirring,thermocouple, addition funnel, and a nitrogen inlet and the apparatuswas purged with nitrogen. DMF (30.0 L) and8-bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 5, 3000 g, 8.98 moles) were charged to the reactor and themixture was stirred at ambient temperature until a solution wasobtained. Potassium carbonate (K₂CO₃, 1371 g, 9.92 moles, 1.11 equiv)and methyl iodide (MeI, 1536 g, 0.67 L, 10.83 moles, 1.21 equiv) werethen charged to the reactor while maintaining the internal temperatureat about 17° C. The resulting reaction mixture was stirred for about 4hours until the methylation reaction completion was indicated by HPLC.Potable water (60.0 L) was charged to the reactor while maintaining theinternal temperature at about 19° C. and the mixture was stirred atambient temperature for about 2.5 hours. The solids were collected byfiltration and the wet cake was washed with potable water (30.0 L) andair-dried for about 15.5 hours followed by drying under vacuum at about45° C. to afford crude8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 6, 2834 g, 3127 g theoretical, 90.6% yield) as off-white toyellow powder, which was used in the subsequent reaction without furtherpurification. Compound 6: ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J=1.9 Hz,1H), 7.59 (d, J=1.9 Hz, 1H), 3.37 (s, 3H), 3.31 (d, J=3.4 Hz, 3H), 1.49(s, 6H) ppm; ¹³C NMR (101 MHz, DMSO-d₆) δ 167.47 (s), 144.14 (s), 136.03(s), 131.46 (s), 126.07 (s), 113.71 (s), 111.25 (s), 79.80 (s), 43.98(s), 29.42 (s), 24.28 (s) ppm.

Synthesis of intermediate Compound 9 was carried out according to Scheme2.

Step 1b.(E)-2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine(Compound 11)

Lithium methanolate (11.5 g, 0.303 moles, 0.147 equiv) in methanol (300mL) was added to a solution of5-bromo-2-methoxy-4-methyl-3-nitropyridine (Compound 10, 508 g, 2.057moles) in DMF (5.0 L). The reaction mixture was heated to 90° C. and1,1-dimethoxy-N,N-dimethylmethanamine (2180 mL, 8.0 equiv) was addedover 10 minutes. The reaction mixture was stirred at 90-95° C.overnight. When LCMS indicated the reaction was complete, the reactionmixture was cooled to 5° C. and ice-cold water (12.2 L) was added froman addition funnel. The mixture was stirred in cooling bath for one hourand the precipitated solids were collected by filtration. The solidswere washed with ice cold water (2 L), suction dried for two hours, thendried under vacuum at 40° C. overnight to afford crude(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine(Compound 11, 506 g, 619.2 g theoretical, 81.7% yield) as red solid,which was used in the subsequent reaction without further purification.Compound 11: ¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.03 (d, J=3.5Hz, 1H), 4.79 (d, J=3.5 Hz, 1H), 3.86 (s, 3H), 2.89 (s, 6H) ppm.

Step 2b. 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 12)

Iron powder (Fe, 1085 g, 19.5 moles, 10 equiv) and acetic acid (HOAc,4380 mL, 4595 g, 76.5 moles, 39.3 equiv) were sequentially added to asolution of(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine(Compound 11, 587 g, 1.95 moles) in tetrahydrofuran (THF, 5.25 L). Thereaction mixture was heated to 40° C., causing a slow and steadyexothermic to 77° C. over one hour. After stirring at 75° C. for anadditional two hours, LCMS indicated the reaction was complete. Thereaction mixture was cooled to 50° C., diluted with ethyl acetate(EtOAc, 4 L) and stirred at room temperature overnight. The solids wereremoved by filtration through celite, which was rinsed with ethylacetate (EtOAc, 6 L). The combined filtrates were concentrated underreduced pressure. The residue was dissolved in ethyl acetate (EtOAc, 16L) and the solution was washed with a solution of sodium carbonate(Na₂CO₃, 900 g) in water (12 L) and with saturated brine (2 L). Thecombined aqueous layers were extracted with ethyl acetate (EtOAc, 4 L).The combined organic layers were evaporated under reduced pressure.Heptanes (4 L) were added and the solvents were removed under reducedpressure to afford crude 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine(Compound 12, 450 g) quantitatively as dark solid, which was used in thesubsequent reaction without further purification. Compound 12: LCMScalculated for C₈H₇BrN₂O (M+H)⁺: 227.0, Found: 227.1; ¹H NMR (300 MHz,DMSO-d₆) δ 7.73 (s, 1H), 7.53 (d, J=3.0 Hz, 1H), 6.40 (d, J=3.0 Hz, 1H),3.99 (s, 3H) ppm.

Step 3b. 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (Compound13)

A 60% dispersion of sodium hydride in mineral oil (NaH, 120 g, 3 moles,1.5 equiv) was added portion-wise over 15 minutes to a solution of crude4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 12, 450 g, 1.95moles) in DMF(4.5 L). The temperature of the reaction mixture reached38° C. The reaction mixture was stirred for 10 minutes before beingcooled to 20° C. p-Toluenesulfonyl chloride (p-TsCl, 562 g, 2.95 moles,1.5 equiv) was added all at once and the mixture was stirred at roomtemperature for two hours. When LCMS indicated the reaction wascomplete, water (9 L) was added. The solids were collected byfiltration, rinsed with water (2.5 L), then dissolved in ethyl acetate(EtOAc, 5 L). The solution was washed with water (3 L). The aqueouslayer was back extracted with ethyl acetate (EtOAc, 3 L). The combinedorganic layers were concentrated under reduced pressure to give crude4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (Compound 13, 801 g)quantitatively as dark solid, which was used in the subsequent reactionwithout further purification. Compound 13: LCMS calculated forC₁₅H₁₃BrN₂O₃S (M+H)⁺: 381.0; Found: 381.0; ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=3.8 Hz, 1H), 7.97 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.43 (d,J=8.5 Hz, 2H), 6.78 (d, J=3.8 Hz, 1H), 3.80 (s, 3H), 2.36 (s, 3H) ppm.

Step 4b. 4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7-ol (Compound 14)

Crude 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (Compound 13,801 g, 1.95 moles) was dissolved in a solution of 4 M HCl in 1,4-dioxane(5.6 L, 22.4 moles, 11.5 equiv) and stirred at 40-45° C. for 12 hours.The reaction mixture was concentrated under reduced pressure and theresidue was suspended in ethyl ether (Et₂O, 1.5 L). The solids werefiltered and washed sequentially with ethyl ether (Et₂O, 0.5 L) andheptanes (1 L) before being dried under vacuum at 40° C. overnight togive crude 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7-ol (Compound 14,648 g, 716 g theoretical, 90.5% yield over three steps) as yellowpowder, which was used in the subsequent reaction without furtherpurification. Compound 14: LCMS calculated for C₁₄H₁₁BrN₂O₃S (M+H)⁺:367.0, Found: 366.9; ¹H NMR (300 MHz, DMSO-d₆) δ 11.46 (s, 1H), 8.01 (d,J=3.5 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.33 (s,1H), 6.57 (d, J=3.5 Hz, 1H), 2.36 (s, 3H) ppm.

Step 5b.4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(Compound 9)

A 60% dispersion of sodium hydride in mineral oil (NaH, 132 g, 3.3moles, 1.2 equiv) was added portion-wise over 15 minutes to a solutionof 4-bromo-1-tosyl-1H-pyrrolo-[2,3-c]pyridin-7-ol (Compound 14, 1000 g,2.72 moles) in DMF (5 L). The temperature of the reaction mixturereached 39° C. After stirring for 30 minutes, the reaction mixture wascooled to 20° C. Iodomethane (MeI, 205 mL, 467 g, 3.3 moles, 1.2 equiv)was added and the reaction mixture was stirred at room temperature for2.5 hours. When LCMS indicated the reaction was complete, water (13 L)was added and the reaction mixture was stirred for 30 minutes. Thesolids were filtered and washed sequentially with water (2.5 L) andheptanes (4 L). The solid was then dissolved in dichloromethane (DCM, 9L) and the solution was transferred into a separation funnel. Theresidual water (˜200 mL) was removed. The dichloromethane solution wastreated with a mixture of sodium sulfate (Na₂SO₄, 200 g), silica gel(SiO₂, 170 g) and activated charcoal (20 g) for one hour. The solidswere removed by filtration through a celite (750 g) pad and the celitepad was washed with dichloromethane (DCM, 3 L). Toluene (1.2 L) wasadded to the combined filtrates. The dichloromethane was removed underreduced pressure. The resulting solids in toluene were collected byfiltration, washed sequentially with toluene (1.2 L) and heptanes (1.2L), and dried under vacuum at 40° C. for 2 hours to give crude4-bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(Compound 9, 728 g, 1036.9 g theoretical, 70.2% yield, 99.3% purity),which was used in the subsequent reaction without further purification.Compound 9: LCMS calculated for C₁₅H₁₃BrN₂O₃S (M+H)⁺: 381.0, Found:381.0; ¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (m, 1H), 7.93 (m, 2H), 7.78 (s,1H), 7.41 (m, 2H), 6.58 (m, 1H), 3.37 (s, 3H), 2.36 (s, 3H) ppm.

Synthesis of Compound 1 was carried out according to Scheme 3

Steps 1 and 2.2,2,4-Trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8)

A 100 L glass reactor was assembled with overhead stirring,thermocouple, addition funnel, and a nitrogen inlet and a 22 L glassreactor was assembled with overhead stirring, condenser, thermocouple,addition funnel, and a nitrogen inlet and each apparatus was purged withnitrogen. 1,4-Dioxane (15.8 L),8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 6, 1008 g, 2.90 moles, 1.05 equiv), bis(pinacolato)diboron(1472 g, 5.80 moles, 2.11 equiv), and potassium acetate (KOAc, 854 g,8.70 moles, 3.16 equiv) were charged to the 100 L reactor. Nitrogen wasbubbled through the reaction mixture for 22 minutes andPd(dppf)Cl₂—CH₂Cl₂ (60.08 g, 0.07 moles, 0.03 equiv) was charged andrinsed into the 100 L reactor with 1,4-dioxane (0.5 L). Nitrogen wasbubbled through the reaction mixture again for 22 minutes. The resultingreaction mixture was heated to gentle reflux (about 81° C.) and stirredat reflux for about 19 hours until the first coupling reactioncompletion was indicated by HPLC. The reaction mixture was then cooledto about 28° C. Separately, a degassed aqueous sodium bicarbonatesolution was prepared by thoroughly mixing sodium bicarbonate (NaHCO₃,578 g, 6.89 moles, 2.50 equiv) and potable water (8.3 L) until asolution was obtained and then bubbling nitrogen through the solutionfor about 34 minutes. The degassed aqueous sodium bicarbonate solutionand 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Compound 9, 1050 g, 2.75 moles) were charged sequentially to the 100 Lreactor at ambient temperature. The resulting reaction mixture in the100 L reactor was heated to gentle reflux (about 89° C.) and stirred atreflux for about 2.5 hours until the second coupling reaction completionwas indicated by HPLC. The reaction mixture was cooled to about 29° C.before potable water (26.3 L) and ethyl acetate (EtOAc, 39.4 L) werecharged. The mixture was stirred at ambient temperature for about 19minutes before being filtered through a Celite (1050 g) bed. The filtercake was washed with ethyl acetate (EtOAc, 4.2 L). The filtrate and washsolution were charged back to the 100 L reactor, the phases wereseparated, and the organic phase was kept in the reactor. Separately, anaqueous sodium bisulfite solution was prepared by thoroughly mixingsodium bisulfite (17,052 g) and potable water (41.0 L). About one thirdof the aqueous sodium bisulfite solution (15.6 L) was charged to theorganic solution in the 100 L reactor and the resulting mixture washeated to about 50° C. and stirred at about 54° C. for about 1 hour. Themixture was cooled to about 39° C. and filtered through the same Celitepad as before, and the filter cake was washed with ethyl acetate (4.2L). The combined filtrate and wash solution were charged back to the 100L reactor, the phases were separated, and the organic phase was kept inthe reactor. About one third of the aqueous sodium bisulfite solution(15.6 L) was charged to the organic solution in the 100 L reactor andthe resulting mixture was heated to about 50° C. and stirred at about52° C. for about 1 hour. The reaction mixture was cooled to about 40°C., the phases were separated, and the organic phase was kept in thereactor. The remainder of the aqueous sodium bisulfite solution (15.6 L)was charged to the organic solution in the 100 L reactor and theresulting mixture was heated to about 50° C. and stirred at about 50° C.for about 1 hour. The mixture was cooled to about 40° C., the phaseswere separated, and the organic phase was kept in the reactor. Theorganic phase was washed sequentially with potable water (10.5 L) andaqueous sodium chloride solution prepared separately from 2100 g ofsodium chloride and 10.5 L of potable water. The organic phase wasconcentrated under reduced pressure at about 42° C. to a target volumeof 11 L remaining (10-12 L per kg of Compound 9 charged). The residuewas transferred to the 22 L reactor. The organic phase was furtherconcentrated under reduced pressure at about 52° C. to a target volumeof 5 L remaining (5-6 L per kg of Compound 9 charged). The residue wascooled to about 24° C. and stirred at about 19° C. for about 11.5 hours.The solids were collected by filtration and the filter cake was washedwith n-heptane (4.2 L) and air-dried for about 4 hours followed byfurther drying under vacuum at about 15-17° C. to afford crude2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 1232 g, 1566.5 g theoretical, 78.6% yield) as yellow tobrown powder, which was combined with the other batches of the crudeCompound 8 produced by the same procedures for the further purificationas described below.

A 100 L glass reactor was assembled with overhead stirring, condenser,thermocouple, addition funnel, and a nitrogen inlet and the apparatuswas purged with nitrogen. Methylene chloride (34 L) and crude2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 3400 g) were charged to the reactor and the mixture wasstirred at about 17° C. until a solution was obtained. Si-Thiol (850 g)was charged to the resulting solution and the mixture was heated toabout 31° C. and stirred at 31° C. for about 2.5 hours. The mixture wasthen cooled to about 20° C. before being filtered. The filter cake waswashed with methylene chloride (14 L) and the combined filtrate and washsolution were concentrated under vacuum at about 32° C. to afford thepurified2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 3728 g) as yellow to brown powder, which has with someorganic solvents and was used directly in the subsequent reactionwithout further drying. Compound 8: ¹H NMR (400 MHz, DMSO-d₆) δ 7.99(dd, J=5.9, 2.3 Hz, 3H), 7.65 (d, J=2.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H),7.56 (s, 1H), 7.44 (d, J=8.2 Hz, 2H), 6.46 (d, J=3.5 Hz, 1H), 3.48 (s,3H), 3.42 (s, 3H), 3.30 (s, 3H), 2.39 (s, 3H), 1.38 (s, 6H) ppm; ¹³C NMR(101 MHz, DMSO-d₆) δ 167.50 (s), 152.60 (s), 145.55 (s), 144.64 (s),136.22 (s), 135.96 (s), 134.83 (s), 131.27 (s), 130.86 (s), 130.07 (s),128.88 (s), 125.37 (s), 124.56 (s), 121.93 (s), 113.72 (s), 108.32 (s),106.83 (s), 79.01 (s), 60.21 (s), 44.17 (s), 36.95 (s), 29.46 (s), 24.28(s), 21.59 (s), 21.22 (s), 14.55 (s) ppm.

Step 3.2,2,4-Trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1)

A 50 L glass reactor was assembled with overhead stirring, distillationapparatus, thermocouple, addition funnel, and a nitrogen inlet and theapparatus was purged with nitrogen. 1,4-Dioxane (10.2 L) and2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 3724 g resulted from the previous step and has solvents,3400 g dry based, 5.97 moles) were charged to the reactor with stirringand the reaction mixture was heated to about 62° C. Separately, anaqueous sodium hydroxide solution was prepared by thoroughly mixingsodium hydroxide (NaOH, 860 g, 21.49 moles, 3.60 equiv) and potablewater (21.5 L). The aqueous sodium hydroxide solution was charged to thereactor over about 26 minutes while maintaining the internal temperatureat below 70° C. The reaction mixture was heated about 84° C. and stirredat about 84° C. for about 2.5 hours until the deprotection reactioncompletion was indicated by HPLC. The reaction mixture was distilledunder reduced pressure at about 70° C. to a target volume of 17 Lremaining (5 L per kg of Compound 8 charged). Potable water (13.6 L) wascharged and the distillation was continued under reduced pressure atabout 76° C. until an additional 7 L (2 L per kg of Compound 8 charged)was collected. The remaining mixture was cooled to about 25° C. andstirred at about 18° C. for about 11 hours. The solids were collected byfiltration and the filter cake was washed with water (34 L) and dried onthe filter for about 1 hour followed by air dried for about 5 days toafford crude2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(compound 1, 1728 g, 2480 g theoretical, 69.7% yield), which waspurified following the procedures described below.

A 50 L glass reactor was assembled with overhead stirring, thermocouple,and a nitrogen inlet and the apparatus was purged with nitrogen.Acetonitrile (17.2 L) and crude2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(crude compound 1, 1726 g, 4.25 moles) were charged to the reactor withstirring. The resulting mixture was heated to about 72° C. and stirredat 70-75° C. for about 1.5 hours. The mixture was then cooled to about25° C. and stirred at ambient temperature for about 1 hour. The solidswere collected by filtration and the filter cake was washed withacetonitrile (9 L) before being charged back to the reactor withacetonitrile (17 L). The mixture was heated to about 39° C. and stirredat about 39° C. for about 1.5 hours. The mixture was cooled to about 17°C. and stirred at 17° C. for about 15 hours. The solids were collectedby filtration and the filter cake was washed with methylene chloride (9L). The product was dried on the filter for about 2 hours followed byair dried for about 1 day to afford the purified2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(compound 1, 1458 g, 1726 g theoretical, 84.5% yield), which wasrecrystallized to afford the desired crystalline form following theprocedures described below.

Step 4. Recrystallization of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1)

A 100 L glass reactor was assembled with overhead stirring,thermocouple, addition funnel, and a nitrogen inlet and a 50 L glassreactor was assembled with overhead stirring, condenser, thermocouple,addition funnel, and a nitrogen inlet and each apparatus was purged withnitrogen. Methanol (18.9 L), Compound 1 (1454 g), and acetone (18.9 L)were charged sequentially to the 100 L reactor with stirring. Theresulting mixture was heated to about 57° C. and stirred at about 57° C.for about 1.25 hours until a clear solution was obtained. The mixturewas transferred through an in-line filter into a clean 50 L reactor. The100 L reactor and filter were rinsed with methanol (2.9 L) through thefilter into the 50 L reactor. The mixture in the 50 L reactor was heatedto about 52° C. and stirred at about 56° C. for about 7 minutes until aclear solution was obtained. The solution in the reactor was thenconcentrated under reduced pressure at about 58° C. to a target volumeof 38 L remaining. The filtered n-heptane (37.7 L) was added to thereactor in portions while maintaining the internal temperature at below60° C. The distillation under reduced pressure was continued at about59° C. to a target volume of 22 L remaining. The remaining mixture wascooled to about 24° C. and stirred at about 17° C. for about 6.75 hours.The solids were collected by filtration and the filter cake was washedwith the filtered n-heptane (7.3 L) and dried on the filter for about 1hour followed by dried under vacuum at 60-65° C. to afford2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(compound 1, 1404 g, 1454 g theoretical, 96.6%) as white to off-whitecrystalline (Form I) powders. Compound 1: mp 266.4° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.13 (s, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.62 (d, J=1.9 Hz,1H), 7.33 (s, 2H), 6.19 (s, 1H), 3.59 (s, 3H), 3.43 (s, 3H), 3.31 (s,3H), 1.41 (s, 6H) ppm; ¹³C NMR (101 MHz, DMSO-d₆) δ 167.66 (s), 154.57(s), 144.55 (s), 134.74 (s), 130.96 (s), 130.33 (s), 129.68 (s), 127.40(s), 126.96 (s), 124.39 (s), 123.53 (s), 113.15 (s), 109.35 (s), 103.07(s), 78.80 (s), 44.22 (s), 36.15 (s), 29.46 (s), 24.26 (s) ppm.

Recrystallization conducted in a mixture of tetrahydrofuran (THF),acetone, and n-heptane using similar procedures as above afford Form IIof the crystalline Compound 1 drug substance was obtained. Both Form Iand Form II have very sharp melting endotherm peaks on DSC, and the twoforms are about one degree difference in peak melting temperature:266.4° C. for Form I and 267.5° C. for Form II. However, Form I and FormII have very different XRD patterns, but both are stable in aqueoussuspension. Studies revealed that Form I is the most stable form in MeOHand acetone while Form II is more stable in IPA. In a mixture ofmethanol, acetone, and n-heptane, Form I and Form II could beinterconverted to each other depending on the conditions such as solventratio, temperature, and time. Form I and Form II of the crystallineCompound 1 have similar solubility in organic solvents and water.

Form I can also be obtained by adding about 30 mg of Compound 1 to about2 mL of saturated or cloudy solution of Compound 1 in acetone followedby stirring at 25±1° C. for 3 days.

An alternative synthesis of Compound 8 was carried out according toScheme 4.

Step 1x.6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Compound 15)

A 500-mL three-necked round-bottomed flask was equipped with a condenserand a nitrogen inlet, which consists of a T-tube assembly connected to amineral oil bubbler. 4-Bromo-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 9, 10.0g, 26.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (13 g, 52mmol, 2.0 equiv),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (Xphos, 1.2 g,2.6 mmol, 0.1 equiv), potassium acetate (5.66 g, 57.7 mmol, 2.2 equiv),and 1,4-dioxane (110 mL) were charged into the flask. The mixture wasdegassed with nitrogen for 5 min. beforetris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃, 600 mg, 0.656 mmol,0.025 equiv) was added to the mixture and the nitrogen degassing wascontinued for 1-2 min. The reaction mixture was then heated to 80° C.and stirred at 80-86° C. for 19 h. When HPLC indicated the reaction wascomplete, the reaction mixture was cooled to room temperature.2-Methoxy-2-methylpropane (MTBE, 50 mL) and silica gel (SiO2, 8 g) wereadded and the mixture was stirred at room temperature for 30 min. Themixture was filtered through a pad of silica gel and the silica gel padwas washed with MTBE. The combined filtrates were concentrated underreduced pressure and the residue was purified by flash column (silicagel, a gradient of 0-80% EtOAc in hexanes) to afford6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Compound 15, 9.5 g, 11.22 g theoretical, 84.7%) as a brown to red oil,which was solidified upon standing at room temperature under vacuum.Compound 15: LCMS calculated for C₂₁H₂₅BN₂O₅S (M+H)⁺, (2M+Na)⁺: m/z429.3, 879.3; Found: 429.1, 879.3.

Step 2x.2,2,4-Trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8)

A solution of8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one(Compound 6, 22.4 g, 64.5 mmol) and6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Compound 15, 29.0 g, 67.7 mmol, 1.05 equiv) in 1,4-dioxane (350 mL) andwater (80 mL) was treated with cesium fluoride (CsF, 33.9 g, 223 mmol,3.46 equiv) and4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(2.0 g, 2.8 mmol, 0.043 equiv) at ambient temperature. The resultingreaction mixture was then degassed three times and each time filled witha steady stream of nitrogen gas. The reaction mixture was then heated toreflux for 2-3 hours. Once HPLC showed the coupling reaction wascomplete, the reaction mixture was gradually cooled down to 30° C.before water (300 mL) and 2-methoxy-2-methylpropane (MTBE, 300 mL) wereadded. The mixture was then stirred at ambient temperature for 15 minbefore the two layers were separated. The aqueous layer was extractedwith methoxy-2-methylpropane (MTBE, 100 mL). The combined extracts weretreated with a solution of sodium bisulfite (40 g) in water (200 mL) andthe resulting mixture was stirred at ambient temperature for 2 hours.The solids were collected by filtration, washed with water, and dried invacuum oven overnight to give the first crop of the desired product,2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 20.0 g, 36.74 g theoretical, 54.4% yield), as off-white toyellow powder, which was used directly in the subsequent reactionwithout further purification.

The two layers of the filtrate were separated, and the organic layer wasdried over MgSO₄ and concentrated under reduced pressure. The residuewas then purified by column chromatography (SiO₂, gradient elution with40-100% EtOAc in hexanes) to give the second crop of the desiredcompound,2,2,4-trimethyl-8-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 8, 13.8 g, 36.74 g theoretical, 37.5 yield; total 33.8 g, 91.9yield), as a pink oil, which was solidified at room temperature undervacuum and was used directly in the subsequent reaction without furtherpurification.

Batches of Compound 8 produced by this alternative synthetic process hasbeen found to be identical to the material produced by the originalsynthesis as described in Scheme 3. This material was subsequentlyconverted to Compound 1 by following the same procedures described inScheme 3.

Example 2. X-Ray Powder Diffraction (XRPD) Studies for Form I and FormII

Form I and Form II of Compound 1 were characterized by XRPD. The XRPDwas obtained from Bruker D2 PHASER X-ray Powder Diffractometerinstrument. The general experimental procedures for XRPD were: (1) X-rayradiation from copper at 1.054056 Å with K_(β) filter and LYNXEYE™detector; (2) X-ray power at 30 kV, 10 mA; and (3) the sample powder wasdispersed on a zero-background sample holder. The general measurementconditions for XRPD were: Start Angle 5 degrees; Stop Angle 30 degrees;Sampling 0.015 degrees; and Scan speed 2 degree/min.

The XRPD pattern of Form I is shown in FIG. 1 and the XRPD data areprovided in Table 1.

TABLE 1 Form I 2-Theta (°) Height H % 7.9 103 0.3 8.7 16238 43.3 9.818668 49.8 10.0 367 1.0 10.2 214 0.6 10.5 137 0.4 11.6 9126 24.3 11.92024 5.4 12.0 1846 4.9 12.7 37515 100 13.6 1284 3.4 14.0 5077 13.5 14.77636 20.4 15.7 13471 35.9 17.5 4552 12.1 17.7 2920 7.8 18.1 1194 3.218.3 3113 8.3 19.2 1170 3.1 19.4 657 1.8 20.0 8378 22.3 21.4 20976 55.921.9 2044 5.4 22.5 6047 16.1 23.3 17466 46.6 23.7 724 1.9 24.2 171 0.525.3 394 1.0 25.4 469 1.3 26.2 2777 7.4 26.5 1191 3.2 27.1 8100 21.628.2 1893 5.0 28.8 2412 6.4 29.2 460 1.2 29.3 533 1.4 29.5 373 1.0

The XRPD pattern of Form II of Compound 1 is shown in FIG. 4 and theXRPD data are provided in Table 2.

TABLE 2 Form II 2-Theta (°) Height H % 6.7 6755 9.3 9.4 2759 3.8 9.55697 7.9 10.5 3305 4.6 13.3 1509 2.1 14.8 15378 21.3 15.1 1751 2.4 15.3630 0.9 15.7 1367 1.9 16.2 22052 30.5 17.0 72319 100 17.1 46591 64.418.2 1945 2.7 18.8 12556 17.4 19.3 36093 49.9 19.7 8478 11.7 20.5 55657.7 21.3 2569 3.6 21.4 995 1.4 21.6 740 1.0 22.0 135 0.2 23.1 7421 10.323.8 7448 10.3 24.4 3308 4.6 24.7 3946 5.5 25.2 3538 4.9 25.3 4287 5.925.7 436 0.6 26.4 3710 5.1 26.8 548 0.8 27.5 9253 12.8 28.3 2614 3.628.5 7520 10.4 29.0 2591 3.6 29.8 1322 1.8 30.4 4664 6.4

Example 3. Differential Scanning Calorimetry (DSC) Studies for Form Iand Form II

Form I and Form II of Compound 1 were characterized by DSC. The DSC wasobtained from TA Instruments Differential Scanning calorimetry, ModelQ2000 with autosampler. The DSC instrument conditions were as follows:25-300° C. at 10° C./min; Tzero aluminum sample pan and lid; andnitrogen gas flow at 50 mL/min.

The DSC thermogram of Form I is shown in FIG. 2. The DSC thermogram ofForm I revealed a major endothermic event at an onset temperature of264.7° C. with a peak temperature of 266.4° C. which is believed to bethe melting/decomposition of the compound.

The DSC thermogram of Form II is shown in FIG. 5. The DSC thermogram ofForm II revealed a major endothermic event at an onset temperature of266.7° C. with a peak temperature of 267.5° C. which is believed to bethe melting/decomposition of the compound.

Example 4. Thermogravimetric Analysis (TGA) Studies for Form I and II

Form I and Form II of Compound 1 were characterized by TGA. The TGA wasobtained from PerkinElmer Thermogravimetric Analyzer, Model Pyris 1. Thegeneral experimental conditions for TGA were: ramp from 25° C. to 350°C. at 10° C./min; nitrogen purge gas flow at 60 mL/min; ceramic cruciblesample holder.

The TGA thermogram of Form I is shown in FIG. 3. A weight loss of about0.4% up to 150° C. was observed and believed to be associated with theloss of moisture or residual solvents. Significant weight loss above250° C. was observed and believed to be associated with thedecomposition of the compound.

The TGA thermogram of Form II is shown in FIG. 6. Significant weightloss above 250° C. was observed and believed to be associated with thedecomposition of the compound.

Example 5. Preparation of Forms Ia, III, IV, V, Va, VI, VII, VIII, IX,X, XI, XII, XIII, XIV, and XV and Amorphous Compound 1

Forms Ia, III, IV, V, Va, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, andXV and Amorphous of Compound 1 were prepared according to the proceduresin Table 3 below. These forms were analyzed by XRPD (see Example 6), DSC(see Example 7), and TGA (see Example 8).

TABLE 3 Solid state form before drying Procedures Form Ia To 16 mL ofheptane was added 4 mL of saturated solution of Compound 1 in acetonefollowed by stirring to give a solid. Form III To about 2 mL ofsaturated or cloudy solution of Compound 1 in acetonitrile was addedabout 30 mg of Compound 1 followed by stirring at 25 ± 1° C. for 3 days.Form IV To about 2 mL of saturated or cloudy solution of Compound 1 inDCM was added about 30 mg of Compound 1 followed by stirring at 25 ± 1°C. for 3 days. Form V To about 2 mL of saturated or cloudy solution ofCompound 1 in 1,4-dioxane was added about 30 mg of Compound 1 followedby stirring at 25 ± 1° C. for 3 days. Form Va To 4.0 mL of saturatedsolution of Compound 1 in 1,4-dioxane was added 16 mL of hexane followedby stirring to give a solid. Form VI To about 2 mL of saturated orcloudy solution of Compound 1 in methanol was added about 30 mg ofCompound 1 followed by stirring at 25 ± 1° C. for 3 days. Form VII Toabout 2 mL of saturated or cloudy solution of Compound 1 in 2-methoxyethanol was added about 30 mg of Compound 1 followed by stirringat 25 ± 1° C. for 3 days. Form VIII Approximately 6 mL of saturatedsolution of Compound 1 in THF was evaporated under air without stirringat 50 ± 1° C. Form IX To about 2 mL of saturated or cloudy solution ofCompound 1 in ethyl acetate was added about 30 mg of Compound 1 followedby stirring at 25 ± 1° C. for 3 days. Form X To about 2 mL of saturatedor cloudy solution of Compound 1 in 2- methoxyethanol was added about 30mg of Compound 1 followed by stirring at 50 ± 1° C. for 2 days. Form XIApproximately 3-4 mL of saturated solution of Compound 1 in chloroformwas evaporated under air without stirring at 25 ± 1° C. Form XIIApproximately 10 mL of saturated solution of Compound 1 in 1-propanolwas evaporated under air without stirring at 50 ± 1° C. Form XIII To 4mL of saturated solution of Compound 1 in acetone was added 16 mL ofheptane followed by stirring to give a solid. Form XIV To 4 mL ofsaturated solution of Compound 1 in acetone was added 16 mL of hexanefollowed by stirring to give a solid. Form XV The sample from Form IIIwas dried under vacuum at 45-50° C. for 28 h. Amorphous Approximately3.5 mL of saturated solution of Compound 1 in 1,4-dioxane wereevaporated under air without stirring at 25 ± 1° C. to give a solid.

Example 6. XRPD of Forms Ia, III, IV, V, Va, VI, VII, VIII, IX, X, XI,XII, XIII, XIV, and XV and Amorphous

XRPD studies were conducted on the various forms from Example 5. TheX-Ray Powder Diffraction (XRPD) was obtained from Rigaku MiniFlex X-rayPowder Diffractometer (XRPD).

The general experimental procedures for XRPD were: (1) X-ray radiationfrom copper at 1.054056 Å with K_(β) filter; (2) X-ray power at 30 KV,15 mA; and (3) the sample powder was dispersed on a zero-backgroundsample holder. The general measurement conditions for XRPD were: StartAngle 3 degrees; Stop Angle 45 degrees; Sampling 0.02 degrees; and Scanspeed 2 degree/min.

FIGS. 7-21 are XRPD patterns of Forms Ia, III, IV, V, Va, VI, VII, VIII,IX, X, XI, XII, XIII, XIV, and XV, respectively. Tables 4-18 are peaklistings of Forms Ia, III, IV, V, Va, VI, VII, VIII, IX, X, XI, XII,XIII, XIV, and XV, respectively. The amorphous solid from Example 6 wasanalyzed using XRPD and determined to be amorphous.

TABLE 4 Form Ia 2-Theta (°) Height H % 7.8 55 9.9 8.8 325 58.5 10.0 36164.9 11.7 140 25.2 12.8 556 100 13.5 513 92.3 14.1 99 17.8 15.8 89 16.016.8 65 11.7 17.7 116 20.9 20.0 329 59.2 20.9 98 17.6 21.5 271 48.7 22.3417 75.0 22.6 556 100 23.3 227 40.8 27.2 187 33.6 28.3 36 6.5 28.9 9316.7 31.8 52 9.4 35.6 58 10.4

TABLE 5 Form III 2-Theta (°) Height H % 7.8 201 26.0 12.4 403 52.2 13.1181 23.4 15.2 297 38.5 15.5 435 56.3 16.9 688 89.1 17.5 772 100 19.1 536.9 20.3 551 71.4 21.0 67 8.7 21.9 70 9.1 22.8 170 22.0 23.5 64 8.3 24.1143 18.5 24.5 218 28.2 25.0 167 21.6 26.9 327 42.4 28.7 74 9.6 29.4 12115.7 30.5 94 12.2 31.1 53 6.9 31.9 45 5.8 32.6 43 5.6 33.4 70 9.1 37.377 10.0 42.8 85 11.0 43.2 45 5.8

TABLE 6 Form IV 2-Theta (°) Height H % 7.0 80 9.4 9.4 97 11.4 10.0 718.4 11.2 167 19.6 16.3 246 28.9 17.5 125 14.7 18.7 196 23.1 20.7 10712.6 22.1 850 100 23.8 85 10.0 25.6 92 10.8 26.2 133 15.6 26.8 232 27.329.0 75 8.8 30.0 78 9.2 35.5 75 8.8 41.9 51 6.0

TABLE 7 Form V 2-Theta (°) Height H % 8.2 452 31.9 8.5 510 36.0 14.1 22515.9 16.3 764 54.0 17.1 1416 100 17.8 127 9.0 18.9 293 20.7 19.8 89563.2 21.4 114 8.1 21.8 337 23.8 22.7 218 15.4 23.8 70 4.9 24.6 127 9.025.8 369 26.1 27.0 41 2.9 27.6 327 23.1 28.5 49 3.5 29.4 131 9.3 29.9290 20.5 32.6 257 18.1 33.1 71 5.0 33.6 38 2.7 34.6 60 4.2 37.8 35 2.538.2 56 4.0 38.6 61 4.3 39.9 57 4.0 40.9 39 2.8 41.7 66 4.7 43.2 78 5.543.6 73 5.2 44.2 44 3.1

TABLE 8 Form Va 2-Theta (°) Height H % 8.7 328 38.2 9.8 55 6.4 12.8 637.3 14.1 51 5.9 16.5 307 35.7 17.3 859 100 19.1 61 7.1 19.9 222 25.820.4 123 14.3 21.6 115 13.4 23.4 48 5.6 24.8 37 4.3 25.9 122 14.2 27.693 10.8 29.9 65 7.6 32.7 68 7.9 43.8 38 4.4

TABLE 9 Form VI 2-Theta (°) Height H % 4.0 156 9.3 8.5 828 49.4 9.6 48529.0 11.4 379 22.6 12.1 1553 92.7 13.5 548 32.7 14.5 460 27.5 15.2 69641.6 17.1 643 38.4 17.7 804 48.0 18.1 242 14.4 19.2 587 35.0 20.7 1675100 21.8 467 27.9 22.6 1467 87.6 23.2 684 40.8 23.9 178 10.6 25.1 32219.2 26.1 878 52.4 28.1 163 9.7 29.3 181 10.8 30.7 450 26.9 32.1 79 4.733.3 190 11.3 35.7 140 8.4 36.5 81 4.8 38.1 147 8.8 41.4 148 8.8 42.6122 7.3

TABLE 10 Form VII 2-Theta (°) Height H % 9.9 678 12.5 12.2 1889 34.814.8 1009 18.6 15.7 666 12.3 16.6 298 5.5 17.0 2239 41.3 17.5 1807 33.317.9 236 4.4 18.2 84 1.5 18.8 5422 100 19.2 538 9.9 19.5 377 7.0 20.21103 20.3 20.8 1072 19.8 21.9 1920 35.4 22.5 207 3.8 22.9 752 13.9 23.3503 9.3 23.7 254 4.7 24.3 131 2.4 24.6 1330 24.5 25.6 2990 55.1 26.6 63211.7 27.9 612 11.3 28.4 491 9.1 28.8 54 1.0 29.3 111 2.0 30.0 342 6.330.9 130 2.4 31.5 240 4.4 32.0 385 7.1 32.4 373 6.9 32.9 198 3.7 33.3222 4.1 33.8 478 8.8 34.5 480 8.9 35.7 236 4.4 37.0 217 4.0 37.7 91 1.738.2 287 5.3 39.0 109 2.0 39.6 124 2.3 40.6 333 6.1 42.4 343 6.3 43.0144 2.7 44.2 544 10.0

TABLE 11 Form VIII 2-Theta (°) Height H % 4.3 148 16.6 8.1 892 100 8.5686 76.9 13.9 43 4.8 16.2 713 79.9 16.6 143 16.0 17.0 891 99.9 17.5 9710.9 18.0 158 17.7 18.9 111 12.4 19.6 664 74.4 20.1 226 25.3 20.5 80 9.021.5 89 10.0 21.8 249 27.9 22.8 47 5.3 23.7 82 9.2 24.4 117 13.1 25.6194 21.7 26.3 41 4.6 27.4 101 11.3 29.3 84 9.4 29.7 92 10.3 30.3 36 4.032.4 138 15.5 32.7 71 8.0 33.4 27 3.0 33.8 29 3.3 34.1 37 4.1 36.2 455.0 37.5 30 3.4 38.3 33 3.7 40.7 30 3.4 41.0 30 3.4 42.5 31 3.5 43.3 485.4

TABLE 12 Form IX 2-Theta (°) Height H % 8.6 182 20.8 9.1 194 22.1 11.4301 34.4 13.4 192 21.9 15.2 212 24.2 16.1 38 4.3 17.1 74 8.4 18.2 82794.4 19.1 89 10.2 20.6 57 6.5 22.1 681 77.7 22.8 378 43.2 23.9 876 10024.3 329 37.6 25.0 89 10.2 26.9 156 17.8 27.3 54 6.2 28.2 43 4.9 28.9 606.8 29.5 75 8.6 30.8 117 13.4 31.3 44 5.0 32.0 85 9.7 35.3 114 13.0 35.931 3.5 36.6 63 7.2 40.0 59 6.7 40.7 44 5.0

TABLE 13 Form X 2-Theta (°) Height H % 4.6 133 0.7 9.8 70 0.4 12.2 1440.7 12.4 235 1.2 14.9 441 2.2 15.3 611 3.1 15.8 554 2.8 17.0 19729 10017.7 1273 6.5 18.3 1632 8.3 18.9 299 1.5 19.7 2260 11.5 20.3 488 2.520.7 352 1.8 20.9 612 3.1 21.5 104 0.5 22.1 126 0.6 22.5 111 0.6 22.9270 1.4 23.5 602 3.1 24.6 141 0.7 24.8 412 2.1 25.4 1339 6.8 26.1 1981.0 26.8 195 1.0 27.5 160 0.8 27.9 210 1.1 29.0 133 0.7 30.0 67 0.3 30.4217 1.1 30.7 194 1.0 31.0 127 0.6 31.7 83 0.4 32.3 3996 20.3 34.0 421021.3 34.8 279 1.4 37.0 1123 5.7 37.5 270 1.4 37.8 76 0.4 38.4 336 1.739.4 684 3.5 39.8 275 1.4 40.6 279 1.4 40.9 1191 6.0 41.7 2101 10.6 42.5173 0.9 43.2 71 0.4 43.9 258 1.3 44.3 475 2.4 44.6 134 0.7

TABLE 14 Form XI 2-Theta (°) Height H % 7.7 95 18.0 8.8 193 36.5 9.6 8616.3 10.8 80 15.1 12.8 265 50.1 14.7 73 13.8 15.8 127 24.0 18.0 376 71.120.6 288 54.4 21.5 442 83.6 22.6 268 50.7 23.3 529 100 26.4 181 34.227.3 168 31.8 31.6 105 19.8

TABLE 15 Form XII 2-Theta (°) Height H % 3.9 215 11.7 5.6 1112 60.3 8.552 2.8 11.2 93 5.0 11.7 448 24.3 12.5 45 2.4 13.8 553 30.0 14.5 591 32.016.3 58 3.1 16.9 299 16.2 17.7 304 16.5 18.7 966 52.4 19.9 52 2.8 21.487 4.7 21.8 99 5.4 23.5 202 10.9 24.6 476 25.8 25.7 79 4.3 27.0 37 2.027.7 55 3.0 29.3 70 3.8 30.1 68 3.7 31.6 41 2.2 34.3 294 15.9 39.8 683.7 42.9 38 2.1 44.2 1845 100 44.6 1468 79.6

TABLE 16 Form XIII 2-Theta (°) Height H % 5.7 87 15.9 8.6 103 18.9 9.871 13.0 11.8 359 65.8 12.6 163 29.9 13.4 142 26.0 14.1 506 92.7 14.8 546100 16.6 182 33.3 17.9 54 9.9 19.1 489 89.6 19.4 169 31.0 19.9 67 12.320.9 82 15.0 21.4 147 26.9 22.4 362 66.3 23.2 81 14.8 24.0 128 23.4 24.9386 70.7 26.3 245 44.9 28.4 44 8.1 28.8 78 14.3 29.8 47 8.6 30.8 21639.6 33.2 36 6.6 34.9 36 6.6

TABLE 17 Form XIV 2-Theta (°) Height H % 4.0 1030 100 5.7 80 7.8 8.0 767.4 8.7 33 3.2 9.8 38 3.7 11.2 932 90.5 11.9 335 32.5 12.7 38 3.7 13.437 3.6 14.1 350 34 14.8 277 26.9 15.9 623 60.5 16.6 166 16.1 17.0 10710.4 17.9 56 5.4 19.1 308 29.9 19.5 147 14.3 19.8 147 14.3 21.0 194 18.821.4 70 6.8 21.9 38 3.7 22.4 173 16.8 23.3 61 5.9 24.0 111 10.8 24.4 11511.2 24.9 349 33.9 26.3 129 12.5 27.2 35 3.4 28.1 109 10.6 28.5 64 6.228.9 94 9.1 29.9 65 6.3 30.9 100 9.7 32.1 38 3.7 33.2 59 5.7 35.6 34 3.343.5 31 3.0

TABLE 18 Form XV 2-Theta (°) Height H % 7.4 192 6.3 7.9 113 3.7 9.6 2036.6 12.4 283 9.2 13.4 923 30.2 15.5 3060 100 16.9 230 7.5 17.7 1713 56.019.0 628 20.5 19.5 881 28.8 20.6 1070 35.0 21.9 554 18.1 22.5 2295 75.023.8 401 13.1 24.3 444 14.5 24.7 382 12.5 25.4 707 23.1 26.2 79 2.6 26.81049 34.3 28.1 655 21.4 29.0 578 18.9 30.0 144 4.7 30.5 331 10.8 31.1328 10.7 31.5 483 15.8 32.3 66 2.2 33.8 217 7.1 34.1 159 5.2 35.4 1725.6 36.0 205 6.7 37.0 66 2.2 38.1 188 6.1 39.8 145 4.7 40.7 143 4.7 42.3268 8.8 42.7 183 6.0 43.4 81 2.6 43.8 90 2.9

Example 7. DSC and TGA Studies of Polymorphic Forms

DSC studies were carried out on Forms Va, VII, VIII, X, XII, XIII, XIV,and XV. The DSC was obtained from TA Instruments Differential Scanningcalorimetry, Model Q200 with autosampler. The DSC instrument conditionswere as follows: 30-300° C. at 10° C./min; Tzero aluminum sample pan andlid; and nitrogen gas flow at 50 mL/min.

TGA studies were carried out on Forms Va, VII, VIII, X, XIII, and XV.The TGA was obtained from TA Instrument Thermogravimetric Analyzer,Model Q500. The general experimental conditions for TGA were: ramp from20° C. to 600° C. at 20° C./min; nitrogen purge, gas flow at 40 mL/minfollowed by balance of the purge flow; sample purge flow at 60 mL/min;platinum sample pan.

Table 19 below shows the results for DSC and TGA.

TABLE 19 Form DSC TGA Va a minor endothermic event at an onset a weightloss of about 0.3% up to 100° C.; temperature of 130° C. with a peaksignificant weight loss above 300° C. temperature of 133° C.; a majorendothermic event at an onset temperature of 266° C. with a peaktemperature of 267° C. VII an endothermic event at an onset a weightloss of about 8% up to 120° C.; temperature and peak temperature ofsignificant weight loss above 300° C. 126° C.; an endothermic event atan onset temperature of 255° C. with a peak temperature of 256° C.; anexothermic event at peak temperature of 260° C.; an endothermic event atan onset temperature of 266° C. with a peak temperature of 267° C. VIIIa minor endothermic event at an onset a weight loss of about 14% up totemperature of 128° C. with a peak 140° C.; temperature of 145° C.;significant weight loss above 300° C. a major endothermic event at anonset temperature of 262° C. with a peak temperature of 265° C. X aminor endothermic event at an onset a weight loss of about 8% up to 120°C.; temperature of 117° C. with a peak significant weight loss above300° C. temperature of 121° C.; a major endothermic event at an onsettemperature of 266° C. with a peak temperature of 267° C. XII anendothermic event at an onset NA temperature of 261° C. with a peaktemperature of 264° C. XIII an endothermic event at an onset a weightloss of about 2% up to 140° C.; temperature of 266° C. with a peaksignificant weight loss above 300° C. temperature of 267° C. XIV anendothermic event at an onset NA temperature of 266° C. with a peaktemperature of 267° C. XV an endothermic event at an onset a weight lossof about 0.4% up to temperature of 57° C. with a peak 150° C.;temperature of 85° C.; significant weight loss above 300° C. anendothermic event at an onset temperature of 164° C. with a peaktemperature of 172° C.; an exothermic event at an onset temperature of183° C. with a peak temperature of 192° C.; a major endothermic event atan onset temperature of 267° C. with a peak temperature of 268° C. NA:not available

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A solid form of a compound having the formula:

wherein the solid form is crystalline; and wherein the solid form isselected from Form Ia, Form III, Form IV, Form V, Form Va, Form VI, FormVII, Form VIII, Form IX, Form X, Form X, Form XI, Form XII, Form XIII,Form XIV, and XV.
 2. The solid form of claim 1, wherein the solid formhas Form Ia.
 3. The solid form of claim 2, having one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 8.8,about 10.0, about 11.7, about 12.8, about 13.5, about 20.0, about 21.5,about 22.6, and about 23.3 degrees.
 4. The solid form of claim 1,wherein the solid form has Form III.
 5. The solid form of claim 4,having one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 7.8, about 12.4, about 13.1, about 15.2, about 15.5,about 16.9, about 17.5, and about 20.3 degrees.
 6. The solid form ofclaim 1, wherein the solid form has Form IV.
 7. The solid form of claim6, having one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 11.2, about 16.3, about 18.7, and about 22.1degrees.
 8. The solid form of claim 1, wherein the solid form has FormV.
 9. The solid form of claim 8, having one or more characteristic XRPDpeaks, in terms of 2-theta, selected from 8.2, about 8.5, about 14.1,about 16.3, about 17.1, about 18.9, about 19.8, about 21.8, and about22.7 degrees.
 10. The solid form of claim 1, wherein the solid form hasForm Va.
 11. The solid form of claim 10, having one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 8.7,about 16.5, about 17.3, about 19.9, and about 21.6 degrees.
 12. Thesolid form of claim 1, wherein the solid form has Form VI.
 13. The solidform of claim 12, having one or more characteristic XRPD peaks, in termsof 2-theta, selected from about 8.5, about 9.6, about 11.4, about 12.1,about 13.5, about 14.5, about 15.2, about 17.1, about 17.7, about 18.1,about 19.2, and about 20.7 degrees.
 14. The solid form of claim 1,wherein the solid form has Form VII.
 15. The solid form of claim 14,having one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 9.9, about 12.2, about 14.8, about 15.7, about 17.0,about 17.5, and about 18.8 degrees.
 16. The solid form of claim 1,wherein the solid form has Form VIII.
 17. The solid form of claim 16,having one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 8.1, about 8.5, about 16.2, about 16.6, about 17.0,about 17.5, about 18.0, about 18.9, about 19.6, and about 20.1 degrees.18. The solid form of claim 1, wherein the solid form has Form IX. 19.The solid form of claim 18, having one or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 8.6, about 9.1, about11.4, about 13.4, about 15.2, about 18.2, about 22.1, about 22.8, andabout 23.9 degrees.
 20. The solid form of claim 1, wherein the solidform has Form X.
 21. The solid form of claim 20, having one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about14.9, about 15.3, about 15.8, about 17.0, about 17.7, about 18.3, andabout 19.7 degrees.
 22. The solid form of claim 1, wherein the solidform has Form XI.
 23. The solid form of claim 22, having one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 8.9,about 12.8, about 18.0 about 21.5, about 22.6, and about 23.3 degrees.24. The solid form of claim 1, wherein the solid form has Form XII. 25.The solid form of claim 24, having one or more characteristic XRPDpeaks, in terms of 2-theta, selected from about 5.6, about 11.7, about13.8, about 14.5, about 16.9, about 17.7, about 18.7, about 23.5, about24.6, about 34.3, about 44.2, and 44.6 degrees.
 26. The solid form ofclaim 1, wherein the solid form has Form XIII.
 27. The solid form ofclaim 26, having one or more characteristic XRPD peaks, in terms of2-theta, selected from about 5.7, about 8.6, about 9.8, about 11.8,about 12.6, about 13.4, about 14.1, about 14.8, about 16.6, and about19.1 degrees.
 28. The solid form of claim 1, wherein the solid form hasForm XIV.
 29. The solid form of claim 28, having one or morecharacteristic XRPD peaks, in terms of 2-theta, selected from about 5.7,about 8.6, about 9.8, about 11.8, about 12.6, about 13.4, about 14.1,about 14.8, about 16.6, and about 19.1 degrees.
 30. The solid form ofclaim 1, wherein the solid form has Form XV.
 31. The solid form of claim30, having one or more characteristic XRPD peaks, in terms of 2-theta,selected from about 7.4, about 9.6, about 12.4, about 13.4, about 15.5,about 16.9, about 17.7, about 19.0, about 19.5, about 20.6, and about22.5 degrees.